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Jiang L, Yi R, Chen H, Wu S. Quercetin alleviates metabolic-associated fatty liver disease by tuning hepatic lipid metabolism, oxidative stress and inflammation. Anim Biotechnol 2025; 36:2442351. [PMID: 39718035 DOI: 10.1080/10495398.2024.2442351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 12/10/2024] [Indexed: 12/25/2024]
Abstract
The natural flavonoid quercetin, which exhibits a range of biological activities, has been implicated in liver disease resistance in recent research. In vivo study attesting to quercetin's protective effect against metabolic-associated fatty liver disease (MAFLD) is inadequate, however. Here, our investigation explored the potential benefits of quercetin in preventing MAFLD in C57BL/6 mice fed a high-fat diet (HFD). The results revealed that quercetin ameliorated the aberrant enhancement of body and liver weight. The hepatic histological anomalie induced by MAFLD were also mitigated by quercetin. HFD-induced imbalance in serum LDL, HDL, AST, ALT, TG, and LDH was mitigated by quercetin. Mechanically, we found that quercetin improved lipid metabolism by reducing lipogenesis proteins including ACC, FASN, and SREBP-1c and enhancing β-oxidation proteins including PPARα and CPT1A. In vitro study demonstrated that quercetin regulated hepatic lipid metabolism by targeting SREBP-1c and PPARα. Additionally, quercetin enhanced the antioxidant capacity in HFD-treated mice by downregulating Nrf2 and HO-1 expressions and upregulating SOD and GPX1 expressions. The hyper-activation of inflammation was also restored by quercetin via eliminating the phosphorylation of IκBα and NF-κB p65. Collectively, our observations highlight that quercetin exerts hepatoprotective properties in MAFLD mice by regulating hepatic lipid metabolism, oxidative stress and inflammatory response.
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Affiliation(s)
- Ling Jiang
- Department of Endocrinology and Metabolism, People's Hospital of Yichun City, Yichun, Jiangxi, People's Republic of China
| | - Rong Yi
- Department of Endocrinology and Metabolism, People's Hospital of Yichun City, Yichun, Jiangxi, People's Republic of China
| | - Huan Chen
- Department of Endocrinology and Metabolism, People's Hospital of Yichun City, Yichun, Jiangxi, People's Republic of China
| | - Shuwu Wu
- Department of Endocrinology and Metabolism, People's Hospital of Yichun City, Yichun, Jiangxi, People's Republic of China
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Chen Y, Liao Z, Mao J, Wang W, Liu Y, Dai W, Wen Z, Liu S, Chen Y, Ma Y, Wang X, Li Z. Discovery of the first-in-class FABP/PPAR multiple modulator for the treatment of metabolic dysfunction-associated steatohepatitis. Eur J Med Chem 2025; 291:117635. [PMID: 40279770 DOI: 10.1016/j.ejmech.2025.117635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 04/09/2025] [Accepted: 04/12/2025] [Indexed: 04/29/2025]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is a complex metabolic syndrome, and the development of new drugs is urgently needed. Fatty acid binding proteins (FABPs) and peroxisome proliferator-activated receptors (PPARs) play an important role in the regulation of lipid absorption, metabolism and inflammation. Considering the synergistic effect of FABP and PPAR in the regulation of MASH pathophysiology, the development of FABP/PPAR multiple modulators might be a promising anti-MASH strategy. Herein, the first-in-class FABP/PPAR multiple modulators were designed by hybrid resveratrol and PPARs agonist Elafibranor. Among them, the compound 27 was identified as the optimal FABP/PPAR multiple modulator (FABP1 IC50 = 0.65 μM, FABP4 IC50 = 1.08 μM, PPARα EC50 = 9.19 μM, PPARγ EC50 = 2.20 μM, PPARδ EC50 = 1.58 μM). Further MST assay confirmed the direct interaction of compound 27 and FABP1, providing a robust validation of its target specificity. In MASH mice, compound 27 exhibited a better therapeutic effect than clinical candidate obeticholic acid in ameliorating multiple pathological features of MASH. This study reported the successful discovery of the first-in-class FABP/PPAR multiple modulators, which provided preliminary evidence that such multi-target agents have broad medical prospects.
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Affiliation(s)
- Ya Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Zibin Liao
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Jianming Mao
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Wenxin Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Yuxia Liu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Wei Dai
- Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, PR China
| | - Zheng Wen
- Department of Emergency, Baiyun Hospital of the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510000, PR China
| | - Sishi Liu
- Department of Gynecology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China
| | - Yayi Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Yiming Ma
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Xiaoying Wang
- Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, PR China.
| | - Zheng Li
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
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Schoen S, Wang M, Dayavansha S, Naja K, Kumar V, Tadross R, Pope K, Ling L, Hunt D, Peters MK, Iafrate A, Mercaldo ND, Sandstrom K, Kim T, Washburn M, Pierce TT, Samir AE. Increased Mechanical Index Improves Shear Wave Elastography: Pilot Study of Signal Enhancement. ULTRASOUND IN MEDICINE & BIOLOGY 2025; 51:1070-1077. [PMID: 40204561 DOI: 10.1016/j.ultrasmedbio.2025.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 02/14/2025] [Accepted: 03/09/2025] [Indexed: 04/11/2025]
Abstract
OBJECTIVE Monitoring liver stiffness is essential for managing chronic liver disease, which poses a major public health challenge. Shear wave elastography (SWE), a non-invasive ultrasound-based technique, is commonly used to quantify liver stiffness. However, its performance can be compromised in individuals with higher body mass indices (BMIs) due to increased ultrasound absorption and distortion. Increasing the intensity of the ultrasound push beam could potentially improve signal quality, but regulatory limits currently restrict this due to safety concerns. This pilot study investigated the efficacy of increasing the push pulse mechanical index (MI) from a conventional value of 1.4 to 2.5 toward improving signal quality, and reducing measurement variability and failure rates. METHODS Healthy volunteers (N=22) stratified by BMI underwent SWE with conventional and increased MI push pulses. The resulting data were processed with conventional SWE algorithms, and the signal and measurement quality of the results were analyzed. RESULTS We found that the higher MI improved the signal-to-noise ratio by 4.6 dB (p<10-4, 95% confidence interval: 3.4-5.8 dB) and reduced the measurement's coefficient of variation by 13% (p<10-4, 95% confidence interval: 5.8%-20.3%), enhancing the success rate of SWE examinations, especially for subjects with a BMI over 30. Liver function tests before and after the SWE examinations showed no signs of bioeffects or harm based on serum biomarkers. CONCLUSION These results suggest that increasing the push pulse MI to 2.5 improves the diagnostic utility of SWE, particularly for individuals with a higher BMI, without introducing significant additional risk. This approach could further enhance SWE's vital role in the monitoring of chronic liver disease at a population scale.
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Affiliation(s)
- Scott Schoen
- Center for Ultrasound Research and Translation, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
| | | | | | - Kim Naja
- Center for Ultrasound Research and Translation, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA
| | | | | | - Kathleen Pope
- Center for Ultrasound Research and Translation, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA
| | - Lauren Ling
- Tufts University School of Medicine, Boston, MA, USA
| | - David Hunt
- Center for Ultrasound Research and Translation, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA
| | - Mary K Peters
- Center for Ultrasound Research and Translation, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA
| | - Ann Iafrate
- Center for Ultrasound Research and Translation, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA
| | - Nathaniel D Mercaldo
- Harvard Medical School, Boston, MA, USA; Department of Radiology, Massachusetts General Hospital, Boston, MA, USA
| | | | | | | | - Theodore T Pierce
- Center for Ultrasound Research and Translation, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Anthony E Samir
- Center for Ultrasound Research and Translation, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
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Hu Y, Li N, Zhang R, Wang J, Fang D, Zhou Q, Zhang H, Cai H, Lu Y. Linghe granules reduces hepatic lipid accumulation in Non-alcoholic fatty liver disease through regulating lipid metabolism and redox balance. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 141:156654. [PMID: 40220422 DOI: 10.1016/j.phymed.2025.156654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 12/15/2024] [Accepted: 03/15/2025] [Indexed: 04/14/2025]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disorder with no approved pharmacological therapies. Linghe granules, a hospital-based formulation derived from a classic prescription, have demonstrated potential in reducing hepatic fat accumulation and improving metabolic health. This study provides a novel, comprehensive assessment of Linghe granules, integrating clinical, preclinical, and molecular analyses for NAFLD management. PURPOSE This study aims to evaluate the therapeutic efficacy of Linghe granules in alleviating NAFLD through an integrated approach. METHODS A clinical trial involving 40 patients with NAFLD was conducted, with participants divided into a control group (lifestyle interventions) and a treatment group (lifestyle interventions plus oral Linghe granules). Various metabolic and liver function indicators were assessed before and after treatment. Additionally, a high-fat diet (HFD) was used to induce a NAFLD model in rat, followed by treatment with different doses of Linghe granules. In vitro studies on HepG2 and L02 cells were performed to the effects of the granules on lipid metabolism. Transcriptomic profiling, Weighted Gene Co-expression Network Analysis (WGCNA), Dynamic Network Biomarkers (DNB) analysis, and molecular docking were employed to explore the underlying mechanisms. RESULTS Linghe granules led to significant reductions in BMI, liver enzymes (AST, ALT), triglycerides, LDL-C, and GGT in patients with NAFLD, accompanied by a notable decrease in hepatic fat accumulation. In the rat model, treatment improved liver weight, liver function, and lipid metabolism. In vitro, Linghe granules decreased lipid accumulation and regulated key lipid metabolism markers, including sterol regulatory element-binding protein 1 (SREBP-1), stearoyl-CoA desaturase 1 (SCD1), and fatty acid-binding protein 5 (FABP5). Mechanistic analyses revealed that Linghe granules modulated oxidative stress-related pathways and genes involved in lipid metabolism. CONCLUSION This study represents the first integrated evaluation of Linghe granules' efficacy and mechanisms in treating NAFLD, demonstrating their potential to improve liver function, reduce lipid accumulation, and modulate key metabolic markers. These results suggest that Linghe granules may serve as an effective adjunctive treatment for NAFLD.
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Affiliation(s)
- Yuting Hu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ni'ao Li
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Rumian Zhang
- Xiamen Hospital of Traditional Chinese Medicine, Xiamen, 361015, China
| | - Jia Wang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Dongdong Fang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qianmei Zhou
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hua Zhang
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Hong Cai
- Xiamen Hospital of Traditional Chinese Medicine, Xiamen, 361015, China.
| | - Yiyu Lu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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5
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Kim HR, Tabiatnejad P, Arestakesyan H, Young CN. Modulation of liver lipid metabolic pathways by central nervous system ER stress. Am J Physiol Endocrinol Metab 2025; 328:E833-E844. [PMID: 40261717 DOI: 10.1152/ajpendo.00392.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 11/11/2024] [Accepted: 04/01/2025] [Indexed: 04/24/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), considered as the hepatic manifestation of metabolic syndrome, can increase the risk for cardiometabolic diseases. Accumulating reports have implicated the central nervous system in MASLD pathogenesis, specifically endoplasmic reticulum (ER) stress in subfornical organ (SFO) to hypothalamic paraventricular nucleus (PVN) projecting neurons (SFO→PVN). Here, we investigated how ER stress in this neural circuit influences hepatic lipid regulatory pathways that may contribute to MASLD development during obesity. Hepatic steatosis was elicited by feeding C57BL/6J male mice a high-fat diet for 11 wk. Intersectional viral targeting was used to inhibit ER stress in SFO→PVN neurons to examine the contribution of ER stress in this circuit to hepatic lipid acquisition and disposal genes during obesity. Inhibition of ER stress in SFO→PVN neurons of obese mice resulted in a reduction in hepatic triglycerides and lipid acquisition genes that was paralleled by a reduction in liver tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis. Moreover, hepatic tyrosine hydroxylase expression was positively correlated with lipid acquisition but not disposal pathways. These results indicate that ER stress in SFO→PVN neurons may contribute to MASLD through sympathetic nervous system influences, primarily on hepatic lipid acquisition.NEW & NOTEWORTHY Endoplasmic reticulum stress in SFO→PVN neurons modulates hepatic lipid acquisition and disposal pathways during obesity-induced hepatic steatosis. Hepatic tyrosine hydroxylase levels are positively correlated with liver triglyceride levels and lipid acquisition pathway-related genes in diet-induced obese animals.
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Affiliation(s)
- Han Rae Kim
- Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
| | - Parisa Tabiatnejad
- Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
| | - Hovhannes Arestakesyan
- Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
| | - Colin N Young
- Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
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Yang L, Zheng SG. Role of regulatory T cells in inflammatory liver diseases. Autoimmun Rev 2025; 24:103806. [PMID: 40139456 DOI: 10.1016/j.autrev.2025.103806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 03/21/2025] [Accepted: 03/21/2025] [Indexed: 03/29/2025]
Abstract
The liver is the human body's largest digestive gland, which can participate in digestion, metabolism, excretion, detoxification and immunity. Chronic liver diseases such as metabolic dysfunction-associated fatty liver disease (MAFLD) or viral hepatitis involve ongoing inflammation and resulting liver fibrosis may ultimately lead to the development of hepatobiliary cancers (HCC). Inflammation is the coordinated reaction of different liver cell types to cell signals and death of inflammation, which are linked to injury pathways within the liver or external agents from the gut-liver axis and the circulation. Regulatory T (Treg) cells play a crucial role in controlling inflammation and are essential for maintaining immune tolerance and balance. In this review, we highlight the recent discoveries related to the function of immune systems in liver inflammation and discuss the role of Treg cells in the different liver diseases (including MAFLD, autoimmune hepatitis and others).
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Affiliation(s)
- Linjie Yang
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523808, China
| | - Song Guo Zheng
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523808, China; Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China; State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 201600, China.
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7
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Gao L, Yang K, Zhao Y, Zhang J, Jiang S, Zhang R, He W, Zhao Y, Ye Q, Xu G. Intestinal L-cell mechanoreception regulates hepatic lipid metabolism through GLP-1. SCIENCE ADVANCES 2025; 11:eadv3201. [PMID: 40446026 PMCID: PMC12124353 DOI: 10.1126/sciadv.adv3201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Accepted: 04/25/2025] [Indexed: 06/02/2025]
Abstract
Glucagon-like peptide-1 (GLP-1), secreted by intestinal L cells, is essential for lowering postprandial glucose levels and regulating hepatic lipid metabolism.We investigate the effects of manipulating Piezo1 in L cells on hepatic lipid metabolism. We found that normal and high-fat diet-fed L cell-specific Piezo1 knockout (IntL-Piezo1-/-) mice exhibited reduced circulating GLP-1 levels, increased hepatic lipid accumulation, decreased β-catenin expression, and elevated lipogenesis-related genes and proteins, including SREBP1c, PPARγ, FASN, and ACC. Treatment with exendin-4 improved fatty liver in IntL-Piezo1-/- mice by stimulating β-catenin and inhibiting de novo lipogenesis. Intestinal bead implantation stimulated GLP-1 release and inhibited lipid synthesis in livers of diet-induced obese mice but not in IntL-Piezo1-/- mice. In primary hepatocytes derived from IntL-Piezo1-/- mice, lipid accumulation and enhanced fatty acid synthesis were associated with reduced β-catenin expression and impaired nuclear translocation. Exendin-4 treatment alleviated lipid accumulation, which was blocked by the β-catenin inhibitor nitazoxanide. L-cell mechanoreception is vital for regulating hepatic lipid metabolism through GLP-1.
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Affiliation(s)
- Luyang Gao
- Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510632, China
| | - Ke Yang
- Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510632, China
| | - Yawen Zhao
- Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510632, China
| | - Jinshan Zhang
- Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510632, China
| | - Shaohua Jiang
- Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510632, China
| | - Rujiao Zhang
- Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510632, China
| | - Wenxin He
- Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510632, China
| | - Yuhang Zhao
- Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510632, China
| | - Qianqian Ye
- Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510632, China
| | - Geyang Xu
- Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510632, China
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, Guangdong 510632, China
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Thomas A, Thomas A. Managing Nonalcoholic Fatty Liver Disease Through Structured Lifestyle Modification Interventions. Am J Lifestyle Med 2025:15598276251346717. [PMID: 40438150 PMCID: PMC12106371 DOI: 10.1177/15598276251346717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 05/14/2025] [Accepted: 05/16/2025] [Indexed: 06/01/2025] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a significant global health burden. It comprises a broad pathological spectrum ranging from simple liver steatosis to steatohepatitis with variable degrees of fibrosis, and liver failure. Patients with NAFLD have an increased risk of liver-related and overall mortality. While the trials to assess the efficacy of the medications are ongoing, lifestyle modification is the first line of therapy recommended. The primary aim of this review paper is to synthesize literature related to current evidence-based lifestyle interventions for preventing and managing NAFLD. The review and synthesis of the literature reveal that personalized nutritional, exercise, and behavior change interventions are effective in managing NAFLD. Evidence suggests that there are several gaps in managing NAFLD. The gaps discussed in this paper include a lack of awareness of the disease, ineffective patient-provider communication, shortage of specialists, under-recognition of the disease, and liver health disparities. This paper highlights the evidence-based opportunities to overcome those gaps, such as utilizing comprehensive models of care, clinical care pathways, and clinical practice guidelines. Primary care physicians and endocrinologists, who are the first point of contact must utilize these opportunities for diagnosing and managing patients with NAFLD.
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Affiliation(s)
- Andrew Thomas
- Internal Medicine, Southern Illinois Healthcare, Carbondale, IL, USA (AT)
| | - Annie Thomas
- Marcella Niehoff School of Nursing, Loyola University Chicago, Maywood, IL, USA (AT)
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Annadurai P, Isaac AE. Unveiling the role of IL7R in metabolism-associated fatty liver disease leading to hepatocellular carcinoma through transcriptomic and machine learning approaches. Discov Oncol 2025; 16:873. [PMID: 40408005 PMCID: PMC12102058 DOI: 10.1007/s12672-025-02638-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Accepted: 05/09/2025] [Indexed: 05/26/2025] Open
Abstract
Dysregulation of hepatic metabolism is a crucial factor in the development of fatty liver disease and significantly increases the risk of hepatocellular carcinoma (HCC). This study aims to identify the genes implicated in the prognosis of HCC among individuals suffering from metabolic fatty liver disease. We analysed protein-protein interaction (PPI) networks and constructed a weighted gene co-expression network analysis (WGCNA) using high-throughput gene expression profiling datasets. Our meta-analysis uncovered 442 differentially expressed genes (DEGs), comprising 30 upregulated and 412 downregulated genes. We constructed a PPI network from the DEGs and identified significant hub genes based on their degree centrality scores. Additionally, WGCNA highlighted impactful genes and tightly correlated modules, leading to the creation of a gene interaction network specific to metabolism-associated fatty liver disease (MAFLD). Pathway analysis revealed the candidate regulatory gene interleukin-7 receptor (IL7R), which is involved in cytokine-mediated signalling across both interaction networks. Pro-inflammatory cytokines interact with IL7R, activating the JAK/STAT pathway that influences gene expression throughout progression to HCC. IL7R activates STAT3, affecting the behaviour of activated hepatic stellate cells following initial liver damage. Furthermore, the expression of the IL7R gene was validated as a predictor of HCC malignancy through a logistic regression model, resulting in an accuracy of 92%. Findings suggest that IL7R could be the target gene associated with metabolism-linked HCC. It could significantly impact the management of metabolic-associated fatty liver disease (MAFLD) and may help enhance HCC diagnostics to improve patient outcomes.
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Affiliation(s)
- Priyadharshini Annadurai
- Bioinformatics Programming Laboratory, Department of Bioscience, School of Bio Science and Technology, Vellore Institute of Technology, Katpadi, Vellore - 632014, Tamil Nadu, India
| | - Arnold Emerson Isaac
- Bioinformatics Programming Laboratory, Department of Bioscience, School of Bio Science and Technology, Vellore Institute of Technology, Katpadi, Vellore - 632014, Tamil Nadu, India.
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10
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Losasso MR, Parussolo MLC, Oliveira Silva A, Direito R, Quesada K, Penteado Detregiachi CR, Bechara MD, Méndez-Sánchez N, Abenavoli L, Araújo AC, de Alvares Goulart R, Guiger EL, Fornari Laurindo L, Maria Barbalho S. Unraveling the Metabolic Pathways Between Metabolic-Associated Fatty Liver Disease (MAFLD) and Sarcopenia. Int J Mol Sci 2025; 26:4673. [PMID: 40429815 PMCID: PMC12111209 DOI: 10.3390/ijms26104673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2025] [Revised: 05/10/2025] [Accepted: 05/12/2025] [Indexed: 05/29/2025] Open
Abstract
Metabolic-Associated Fatty Liver Disease (MAFLD) is a public health concern that is constantly expanding, with a fast-growing prevalence, and it affects about a quarter of the world's population. This condition is a significant risk factor for cardiovascular, hepatic, and oncologic diseases, such as hypertension, hepatoma, and atherosclerosis. Sarcopenia was long considered to be an aging-related syndrome, but today, it is acknowledged to be secondarily related to chronic diseases such as metabolic syndrome, cardiovascular conditions, and liver diseases, among other comorbidities associated with insulin resistance and chronic inflammation, besides inactivity and poor nutrition. The physiopathology involving MAFLD and sarcopenia has still not been solved. Inflammation, oxidative stress, mitochondrial dysfunction, and insulin resistance seem to be some of the keys to this relationship since this hormone target is mainly the skeletal muscle. This review aimed to comprehensively discuss the main metabolic and physiological pathways involved in these conditions. MAFLD and sarcopenia are interconnected by a complex network of pathophysiological mechanisms, such as insulin resistance, skeletal muscle tissue production capacity, chronic inflammatory state, oxidative stress, and mitochondrial dysfunction, which are the main contributors to this relationship. In addition, in a clinical analysis, patients with sarcopenia and MAFLD manifest more severe hepatitis fibrosis when compared to patients with only MAFLD. These patients, with both disorders, also present clinical improvement in their MAFLD when treated for sarcopenia, reinforcing the association between them. Lifestyle changes accompanied by non-pharmacological interventions, such as dietary therapy and increased physical activity, undoubtedly improve this scenario.
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Affiliation(s)
- Marina Ribas Losasso
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Maria Luiza Cesto Parussolo
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Antony Oliveira Silva
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Rosa Direito
- Laboratory of Systems Integration Pharmacology, Clinical and Regulatory Science, Research Institute for Medicines, Universidade de Lisboa (iMed.ULisboa), Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal
| | - Karina Quesada
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Claudia Rucco Penteado Detregiachi
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Marcelo Dib Bechara
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico
| | - Ludovico Abenavoli
- Department of Health Sciences, University “Magna Graecia”, Viale Europa, 88100 Catanzaro, Italy
| | - Adriano Cressoni Araújo
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Ricardo de Alvares Goulart
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Elen Landgraf Guiger
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Lucas Fornari Laurindo
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Sandra Maria Barbalho
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Department of Biochemistry and Nutrition, School of Food and Technology of Marília (FATEC), Marília 17500-000, SP, Brazil
- Research Coordinator, UNIMAR Charity Hospital, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
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11
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Kido H, Mizukoshi E, Yanagi M, Shihui L, Seike T, Nakagawa H, Yamashima T, Shiraishi Y, Ozaki N, Harada K, Okada H, Goto H, Kimura K, Yamamoto Y, Yamashita T. Abnormalities of intracellular organelles in metabolic dysfunction-associated steatotic disease. J Gastroenterol 2025:10.1007/s00535-025-02257-5. [PMID: 40343540 DOI: 10.1007/s00535-025-02257-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 04/25/2025] [Indexed: 05/11/2025]
Abstract
BACKGROUND The concept of metabolic dysfunction-associated steatotic disease (MASLD) is increasingly being recognized. The mechanisms contributing to hepatocellular injury include oxidative stress owing to mitochondrial dysfunction, endoplasmic reticulum (ER) stress owing to abnormal protein accumulation in the rough ER, and disruption of cellular homeostasis and metabolic regulation to autophagic dysfunction. However, the morphological abnormalities of these intracellular organelles remain unclear. METHODS Liver tissues from model mice of MASLD, patients with MASLD, and respective controls were subjected to histopathological examination using light microscopy, and intracellular organelles were analyzed via transmission electron microscopy (TEM). RESULTS In model mice of MASLD, the progression of MASLD pathology was associated with abnormalities in mitochondria, glycogen granules, and rough ER. Based on these findings, the electron microscopic observations of these intracellular organelles were classified, weighted, and evaluated in liver tissues of patients with MASLD. The electron microscopic findings were significantly relatively frequent in patients with MASLD and correlated with existing histopathological scoring. CONCLUSIONS Using TEM, we identified characteristic abnormalities in intracellular organelles specific to MASLD. These findings contribute to the understanding of the mechanisms underlying hepatocellular injury in MASLD.
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Affiliation(s)
- Hidenori Kido
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan.
| | - Masahiro Yanagi
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Li Shihui
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Takuya Seike
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hidetoshi Nakagawa
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Tetsumori Yamashima
- Department of Psychiatry and Behavioral Science, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yoshitake Shiraishi
- Department of Functional Anatomy, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Noriyuki Ozaki
- Department of Functional Anatomy, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Kenichi Harada
- Department of Human Pathology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hikari Okada
- Information-Based Medicine Development, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hisanori Goto
- Department of Biochemistry and Molecular Vascular Biology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Kumi Kimura
- Department of Biochemistry and Molecular Vascular Biology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yasuhiko Yamamoto
- Department of Biochemistry and Molecular Vascular Biology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Taro Yamashita
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
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12
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Abbaszadeh M, Hosseinpanah F, Tohidi M, Karimpour Reyhan S, Mahdavi M, Valizadeh M. Sex-Specific Impact of Metabolic Dysfunction-Associated Fatty Liver Disease on Incident Cardiovascular Diseases and Mortality. Endocrinol Diabetes Metab 2025; 8:e70035. [PMID: 40140729 PMCID: PMC11946537 DOI: 10.1002/edm2.70035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 12/30/2024] [Accepted: 02/02/2025] [Indexed: 03/28/2025] Open
Abstract
BACKGROUND AND AIMS Considering recent revisions in the nomenclature for fatty liver disease, alongside limited data on sex-specific differences in its cardiovascular/mortality outcomes, this study aims to investigate the prevalence and impact of metabolic-associated fatty liver disease (MAFLD) on cardiovascular disease (CVD) and mortality in men and women over a 12-year follow-up period. METHODS In this large population-based cohort study, 7101 individuals aged ≥ 30 were enrolled. The prevalence of MAFLD was investigated in both genders. After excluding individuals with a history of previous CVD, 6331 participants were followed up for CVD and mortality over 12 years. Steatosis was defined as fatty liver index (FLI) ≥ 60. Multivariate-adjusted hazard ratios (HRs) were calculated for CVD and mortality. RESULTS The prevalence of MAFLD was 43.2%, higher in men (46.5%) than women (40.6%). Men with MAFLD (47.7 ± 12.1) were younger than women (52.2 ± 11.1). In the 12-year follow-up of 6331 individuals, multivariable-adjusted CVD HRs for MAFLD were 1.36 (1.10-1.67) in men and 1.48 (1.16-1.88) in women. Adjusted mortality HRs were 1.17 (0.86-1.59) and 1.38 (1.00-1.91) in men and women, respectively. Among patients with MAFLD, a subgroup with diabetes faced the highest hazard for CVD and mortality. CONCLUSION This study found that MAFLD is more common in men at a younger age. Despite the higher prevalence in men, women with MAFLD face a greater risk of cardiovascular events and mortality. Findings highlight the importance of gender-specific considerations in primary prevention programmes for MAFLD-related cardiovascular disease and mortality.
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Affiliation(s)
- Mahsa Abbaszadeh
- Endocrinology and Metabolism Research CenterImam Khomeini Hospital Complex, Tehran University of Medical SciencesTehranIran
| | - Farhad Hosseinpanah
- Obesity Research CenterResearch Institute for Endocrine Sciences, Shahid Beheshti University of Medical ScienceTehranIran
| | - Maryam Tohidi
- Prevention of Metabolic Disorders Research CenterResearch Institute for Endocrine Sciences, Shahid Beheshti University of Medical SciencesTehranIran
| | - Sahar Karimpour Reyhan
- Endocrinology and Metabolism Research CenterImam Khomeini Hospital Complex, Tehran University of Medical SciencesTehranIran
| | - Maryam Mahdavi
- Obesity Research CenterResearch Institute for Endocrine Sciences, Shahid Beheshti University of Medical ScienceTehranIran
| | - Majid Valizadeh
- Obesity Research CenterResearch Institute for Endocrine Sciences, Shahid Beheshti University of Medical ScienceTehranIran
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13
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Meneses JP, Qadir A, Surendran N, Arrieta C, Tejos C, Andia ME, Chen Z, Uribe S. Unbiased and reproducible liver MRI-PDFF estimation using a scan protocol-informed deep learning method. Eur Radiol 2025; 35:2843-2854. [PMID: 39500799 DOI: 10.1007/s00330-024-11164-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 08/30/2024] [Accepted: 09/29/2024] [Indexed: 04/25/2025]
Abstract
OBJECTIVE To estimate proton density fat fraction (PDFF) from chemical shift encoded (CSE) MR images using a deep learning (DL)-based method that is precise and robust to different MR scanners and acquisition echo times (TEs). METHODS Variable echo times neural network (VET-Net) is a two-stage framework that first estimates nonlinear variables of the CSE-MR signal model, to posteriorly estimate water/fat signal components using the least-squares method. VET-Net incorporates a vector with TEs as an auxiliary input, therefore enabling PDFF calculation with any TE setting. A single-site liver CSE-MRI dataset (188 subjects, 4146 axial slices) was considered, which was split into training (150 subjects), validation (18), and testing (20) subsets. Testing subjects were scanned using several protocols with different TEs, which we then used to measure the PDFF reproducibility coefficient (RDC) at two regions of interest (ROIs): the right posterior and left hepatic lobes. An open-source multi-site and multi-vendor fat-water phantom dataset was also used for PDFF bias assessment. RESULTS VET-Net showed RDCs of 1.71% and 1.04% on the right posterior and left hepatic lobes, respectively, across different TEs, which was comparable to a reference graph cuts-based method (RDCs = 1.71% and 0.86%). VET-Net also showed a smaller PDFF bias (-0.55%) than graph cuts (0.93%) when tested on a multi-site phantom dataset. Reproducibility (1.94% and 1.59%) and bias (-2.04%) were negatively affected when the auxiliary TE input was not considered. CONCLUSION VET-Net provided unbiased and precise PDFF estimations using CSE-MR images from different hardware vendors and different TEs, outperforming conventional DL approaches. KEY POINTS Question Reproducibility of liver PDFF DL-based approaches on different scan protocols or manufacturers is not validated. Findings VET-Net showed a PDFF bias of -0.55% on a multi-site phantom dataset, and RDCs of 1.71% and 1.04% at two liver ROIs. Clinical relevance VET-Net provides efficient, in terms of scan and processing times, and unbiased PDFF estimations across different MR scanners and scan protocols, and therefore it can be leveraged to expand the use of MRI-based liver fat quantification to assess hepatic steatosis.
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Affiliation(s)
- Juan P Meneses
- Biomedical Imaging Center, Pontificia Universidad Católica de Chile, Santiago, Chile
- i-HEALTH Millennium Institute for Intelligent Healthcare Engineering, Santiago, Chile
- Department of Electrical Engineering, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Ayyaz Qadir
- Department of Medical Imaging and Radiation Sciences, Monash University, Melbourne, VIC, Australia
| | - Nirusha Surendran
- Department of Medical Imaging and Radiation Sciences, Monash University, Melbourne, VIC, Australia
| | - Cristobal Arrieta
- i-HEALTH Millennium Institute for Intelligent Healthcare Engineering, Santiago, Chile
- Faculty of Engineering, Universidad Alberto Hurtado, Santiago, Chile
| | - Cristian Tejos
- Biomedical Imaging Center, Pontificia Universidad Católica de Chile, Santiago, Chile
- i-HEALTH Millennium Institute for Intelligent Healthcare Engineering, Santiago, Chile
- Department of Electrical Engineering, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marcelo E Andia
- i-HEALTH Millennium Institute for Intelligent Healthcare Engineering, Santiago, Chile
- School of Medicine and Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Zhaolin Chen
- Monash Biomedical Imaging, Monash University, Melbourne, VIC, Australia
- Department of Data Science and AI, Monash University, Melbourne, VIC, Australia
| | - Sergio Uribe
- Biomedical Imaging Center, Pontificia Universidad Católica de Chile, Santiago, Chile.
- Department of Medical Imaging and Radiation Sciences, Monash University, Melbourne, VIC, Australia.
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14
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Zuo G, Li M, Guo X, Wang L, Yao Y, Huang JA, Liu Z, Lin Y. Fu brick tea supplementation ameliorates non-alcoholic fatty liver disease and associated endotoxemia via maintaining intestinal homeostasis and remodeling hepatic immune microenvironment. Food Res Int 2025; 209:116207. [PMID: 40253128 DOI: 10.1016/j.foodres.2025.116207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 01/27/2025] [Accepted: 03/11/2025] [Indexed: 04/21/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a prevalent disorder of excessive fat accumulation and inflammation in the liver that currently lacks effective therapeutic interventions. Fu brick tea (FBT) has been shown to ameliorate liver damage and modulate gut microbiota dysbiosis in NAFLD, but the potential mechanisms have not been comprehensively elucidated, especailly whether its hepatoprotective effects are determined to depend on the homeostasis of gut microbiota, intestinal barrier function and hepatic immune microenvironment. In this study, our results further demonstrated that FBT not only alleviated NAFLD symptoms and related endotoxemia in high-fat diet (HFD)-fed rats, but also attenuated intestinal barrier dysfunction and associated inflammation, also confirmed in Caco-2 cell experiment. Meanwhile, FBT intervention significantly relieved HFD-induced gut microbiota dysbiosis, characterized by increased diversity and composition, particularly facilitating beneficial microbes, including short chain fatty acids (SCFAs) and bile acids producers, such as Blautia and Fusicatenibacter, and inhibiting Gram-negative bacteria, such as Prevotella_9 and Phascolarctobacterium. Also, the gut microbiota-dependent hepatoprotective effects of FBT were verified by fecal microbiota transplantation (FMT) experiment. Thus, the beneficial moulation of gut microbiota altered by FBT in levels of SCFAs, bile acids and lipopolysaccharides, intestinal barrier function and TLR4/NF-κB pathway contributed to alleviate liver steatosis and inflammation. Additionally, the hepatoprotective effects of FBT was further demonstrated by suppressing Kupffer cell activation and regulating lipid metabolism using an ex vivo model of liver organoid. Therefore, FBT supplementation can maintain intenstinal homeostasis and remodel hepatic immune microenvironment to prevent NAFLD and associated endotoxemia.
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Affiliation(s)
- Gaolong Zuo
- Key Laboratory of Tea Science of Ministry of Education and Co-Innovation Centre of Education Ministry for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, PR China; National Research Center of Engineering & Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, PR China
| | - Menghua Li
- Key Laboratory of Tea Science of Ministry of Education and Co-Innovation Centre of Education Ministry for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, PR China; National Research Center of Engineering & Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, PR China
| | - Xiaoli Guo
- Key Laboratory of Tea Science of Ministry of Education and Co-Innovation Centre of Education Ministry for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, PR China; National Research Center of Engineering & Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, PR China
| | - Ling Wang
- Key Laboratory of Tea Science of Ministry of Education and Co-Innovation Centre of Education Ministry for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, PR China; National Research Center of Engineering & Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, PR China
| | - Yanyan Yao
- Key Laboratory of Tea Science of Ministry of Education and Co-Innovation Centre of Education Ministry for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, PR China; National Research Center of Engineering & Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, PR China
| | - Jian-An Huang
- Key Laboratory of Tea Science of Ministry of Education and Co-Innovation Centre of Education Ministry for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, PR China; National Research Center of Engineering & Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, PR China; Key Laboratory for Evaluation and Utilization of Gene Resources of Horticultural Crops, Ministry of Agriculture and Rural Affairs of China, Hunan Agricultural University, Changsha 410128, PR China.
| | - Zhonghua Liu
- Key Laboratory of Tea Science of Ministry of Education and Co-Innovation Centre of Education Ministry for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, PR China; National Research Center of Engineering & Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, PR China; Key Laboratory for Evaluation and Utilization of Gene Resources of Horticultural Crops, Ministry of Agriculture and Rural Affairs of China, Hunan Agricultural University, Changsha 410128, PR China.
| | - Yong Lin
- Key Laboratory of Tea Science of Ministry of Education and Co-Innovation Centre of Education Ministry for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, PR China; National Research Center of Engineering & Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, PR China; Key Laboratory for Evaluation and Utilization of Gene Resources of Horticultural Crops, Ministry of Agriculture and Rural Affairs of China, Hunan Agricultural University, Changsha 410128, PR China.
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15
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Zhang M, Ji J, Lei Y, Qin F, Tao Y, Li N, Bian J, Li Z, Lai M, Qiu Z. Dual inhibition of hepatic ACLY and ACSS2: A synergistic approach to combat NAFLD through lipogenesis reduction and mitochondrial enhancement. Pharmacol Res 2025; 215:107706. [PMID: 40127788 DOI: 10.1016/j.phrs.2025.107706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/28/2025] [Accepted: 03/18/2025] [Indexed: 03/26/2025]
Abstract
Inhibiting de novo lipogenesis (DNL) in hepatocytes is a promising strategy for treating metabolic fatty liver diseases. ACLY, a key enzyme in the DNL pathway, has become a therapeutic target for non-alcoholic fatty liver disease (NAFLD). However, its inhibition shows mixed outcomes, depending on interventions and diets. Evidence suggests ACLY inhibition activates the ACSS2-mediated acetate metabolism and the subsequent DNL, though potential mechanisms and possible consequences remain unclear. This study found that targeting hepatic ACLY with AAV8-shRNA failed to improve NAFLD in mice fed a high-fat, high-fructose diet. Instead, it worsened inflammation and liver injury. ACLY inhibition conditionally upregulated DNL enzymes, but consistently activated the ACSS2-acetyl-CoA pathway and suppressed fatty acid oxidation. Further, ACLY inhibition led to polyunsaturated fatty acid accumulation, triggering mitochondrial dysfunction. The resulting ROS redirected carbon flux into acetate, activating the ACSS2-acetyl-CoA pathway, which promoted lipid biosynthesis and exacerbated mitochondrial dysfunction-a vicious cycle that fueled inflammation and liver damage. Dual inhibition of ACLY and ACSS2 broke this cycle by reducing hepatic acetyl-CoA flux, suppressing DNL, enhancing fatty acid oxidation via PPAR-α activation, and improving mitochondrial function. This combined targeting strategy reduced lipid accumulation, alleviated inflammation, and normalized aminotransferase levels, effectively reversing NAFLD progression.
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Affiliation(s)
- Mengdi Zhang
- School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Jinliang Ji
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yuanyuan Lei
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Fujian Qin
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yitong Tao
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Ning Li
- National Experimental Teaching Demonstration Center of Pharmacy, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Jinlei Bian
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Zhiyu Li
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Maode Lai
- School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Disease Proteomics of Zhejiang Province, Department of Pathology, Zhejiang University School of Medicine, Hangzhou 310058, China; Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Department of Pathology, Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Zhixia Qiu
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
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16
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García-Beltrán A, Lozano Melero A, Martínez Martínez R, Porres Foulquie JM, López Jurado Romero de la Cruz M, Kapravelou G. A Systematic Review of the Beneficial Effects of Berry Extracts on Non-Alcoholic Fatty Liver Disease in Animal Models. Nutr Rev 2025; 83:819-841. [PMID: 39365946 PMCID: PMC11986334 DOI: 10.1093/nutrit/nuae132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/06/2024] Open
Abstract
CONTEXT Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries and is strongly associated with several metabolic disorders. Plant-derived bioactive extracts, such as berry extracts, with high antioxidant capacity have been used for the treatment and prevention of this pathology. Moreover, they promote circular economy and sustainability. OBJECTIVE To study the beneficial effects of extracts from different parts of berry plants in animal models of NAFLD. DATA SOURCES A systematic research of the MEDLINE (via PubMed), Cochrane, and Scopus databases was conducted to identify relevant studies published after January 2011. In vivo animal studies of NAFLD were included in which berry extracts of different parts of the plant were administered and significantly improved altered biomarkers related to the pathology, such as lipid metabolism and hepatic steatosis, glucose and glycogen metabolism, and antioxidant and anti-inflammatory biomarkers. DATA EXTRACTION Of a total of 203 articles identified, 31 studies were included after implementation of the inclusion and exclusion criteria. DATA ANALYSIS Most of the studies showed a decrease in steatosis and a stimulation of genes related to β-oxidation and downregulation of lipogenic genes, with administration of berry extracts. Berry extracts also attenuated inflammation and oxidative stress. CONCLUSIONS Administration of berry extracts seems to have promising potential in the design of enriched foodstuffs or nutraceuticals for the treatment of NAFLD.
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Affiliation(s)
- Alejandro García-Beltrán
- Department of Physiology, Biomedical Research Center, Instituto mixto de Deporte y Salud, University of Granada, 18007 Granada, Spain
| | - Aida Lozano Melero
- Department of Physiology, Biomedical Research Center, Instituto mixto de Deporte y Salud, University of Granada, 18007 Granada, Spain
| | - Rosario Martínez Martínez
- Department of Physiology, Biomedical Research Center, Instituto mixto de Deporte y Salud, University of Granada, 18007 Granada, Spain
| | | | | | - Garyfallia Kapravelou
- Department of Physiology, Faculty of Health Sciences, Campus of Melilla, University of Granada, 52005 Granada, Spain
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17
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Cao R, Zhang Y, Cao L, Jiang H. Is type 2 diabetes a link between lung function and metabolic dysfunction-associated steatotic liver disease? Insights from population studies and Mendelian randomization. Eur J Gastroenterol Hepatol 2025; 37:652-659. [PMID: 39976012 DOI: 10.1097/meg.0000000000002941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
AIM This study aimed to investigate the relationship between lung function and metabolic dysfunction-associated steatotic liver disease (MASLD), and the potential mediating role of type 2 diabetes. METHODS Data from the 2007 to 2012 National Health and Nutrition Examination Survey were used. Logistic regression analysis was employed to assess the association between lung function parameters [forced vital capacity (FVC), forced expiratory volume in 1 s (FEV 1 ), FEV 1 /FVC] and MASLD prevalence while exploring type 2 diabetes mediation. Further analyses included linkage disequilibrium score regression, Mendelian randomization, and meta-analysis to examine the causal relationship between lung function and MASLD, considering type 2 diabetes mediation. RESULTS The results showed that higher FVC and FEV 1 levels were associated with decreased MASLD risk, with type 2 diabetes partially mediating this relationship. Genetic analyses supported a causal link between lung function and MASLD, with type 2 diabetes acting as an intermediary. However, no significant association was found between FEV 1 /FVC and MASLD. CONCLUSION The study identified a causal relationship between lung function and MASLD, with type 2 diabetes playing a partial mediating role.
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Affiliation(s)
- Runmin Cao
- Graduate School, Jinzhou Medical University (Jinzhou Central Hospital), Jinzhou, Liaoning Province
| | - Yurun Zhang
- Department of Rehabilitation Therapy, Shandong Xiandai University, Jinan, Shandong Province
| | - Ling Cao
- Department of Chronic Disease Prevention and Control, Jieshou City Center for Disease Control and Prevention, Fuyang
| | - Honghe Jiang
- Department of Clinical Medicine, Anhui University of Science and Technology, Huainan, Anhui Province, China
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18
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Vianna P, Mehrbod P, Chaudhary M, Eickenberg M, Wolf G, Belilovsky E, Tang A, Cloutier G. Unsupervised Test-Time Adaptation for Hepatic Steatosis Grading Using Ultrasound B-Mode Images. IEEE TRANSACTIONS ON ULTRASONICS, FERROELECTRICS, AND FREQUENCY CONTROL 2025; 72:601-611. [PMID: 40138246 DOI: 10.1109/tuffc.2025.3555180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
Ultrasound (US) is considered a key modality for the clinical assessment of hepatic steatosis (i.e., fatty liver) due to its noninvasiveness and availability. Deep learning methods have attracted considerable interest in this field, as they are capable of learning patterns in a collection of images and achieve clinically comparable levels of accuracy in steatosis grading. However, variations in patient populations, acquisition protocols, equipment, and operator expertise across clinical sites can introduce domain shifts that reduce model performance when applied outside the original training setting. In response, unsupervised domain adaptation techniques are being investigated to address these shifts, allowing models to generalize more effectively across diverse clinical environments. In this work, we propose a test-time batch normalization (TTN) technique designed to handle domain shift, especially for changes in label distribution, by adapting selected features of batch normalization (BatchNorm) layers in a trained convolutional neural network model. This approach operates in an unsupervised manner, allowing robust adaptation to new distributions without access to label data. The method was evaluated on two abdominal US datasets collected at different institutions, assessing its capability in mitigating domain shift for hepatic steatosis classification. The proposed method reduced the mean absolute error in steatosis grading by 37% and improved the area under the receiver operating characteristic curves (AUC) for steatosis detection from 0.78 to 0.97, compared to nonadapted models. These findings demonstrate the potential of the proposed method to address domain shift in US-based hepatic steatosis diagnosis, minimizing risks associated with deploying trained models in various clinical settings.
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19
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Wang W, Gao X, Niu W, Yin J, He K. Targeting Metabolism: Innovative Therapies for MASLD Unveiled. Int J Mol Sci 2025; 26:4077. [PMID: 40362316 PMCID: PMC12071536 DOI: 10.3390/ijms26094077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 04/01/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
The recent introduction of the term metabolic-dysfunction-associated steatotic liver disease (MASLD) has highlighted the critical role of metabolism in the disease's pathophysiology. This innovative nomenclature signifies a shift from the previous designation of non-alcoholic fatty liver disease (NAFLD), emphasizing the condition's progressive nature. Simultaneously, MASLD has become one of the most prevalent liver diseases worldwide, highlighting the urgent need for research to elucidate its etiology and develop effective treatment strategies. This review examines and delineates the revised definition of MASLD, exploring its epidemiology and the pathological changes occurring at various stages of the disease. Additionally, it identifies metabolically relevant targets within MASLD and provides a summary of the latest metabolically targeted drugs under development, including those in clinical and some preclinical stages. The review finishes with a look ahead to the future of targeted therapy for MASLD, with the goal of summarizing and providing fresh ideas and insights.
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Affiliation(s)
- Weixin Wang
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
| | - Xin Gao
- School of Public Health, Jilin University, Changchun 130021, China;
| | - Wentong Niu
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
| | - Jinping Yin
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130041, China;
| | - Kan He
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
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20
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Fulda ES, Portas L, Harper C, Preiss D, Bennett D, Doherty A. Association of Daily Steps with Incident Non-Alcoholic Fatty Liver Disease: Evidence from the UK Biobank Cohort. Med Sci Sports Exerc 2025:00005768-990000000-00789. [PMID: 40279651 PMCID: PMC7617666 DOI: 10.1249/mss.0000000000003738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/27/2025]
Abstract
PURPOSE Low physical activity has been shown to be associated with higher risk of non-alcoholic fatty liver disease (NAFLD). However, the strength and shape of this association are currently uncertain due to a reliance on self-reported physical activity measures. This report aims to investigate the relationship of median daily step count with NAFLD using accelerometer-derived step count from a large prospective cohort study. METHODS The wrist-worn accelerometer sub-study of the UK Biobank (N = ~100,000) was used to characterise median daily step count over a seven-day period. NAFLD cases were ascertained via record linkage with hospital inpatient data and death registers or by using a measure of liver fat from imaging. Cox proportional hazards models were employed to assess the association between step count and NAFLD, adjusting for age, sociodemographic, and lifestyle factors. Mediation analyses were conducted. RESULTS Among 91,031 participants (709,440 person-years of follow-up), there were 762 incident NAFLD cases. Higher step count was log-linearly and inversely associated with risk of NAFLD. A 1000-step increase (representing 10 minutes of walking) was associated with a 12% (95% CI: 10%-14%) lower hazard of NAFLD. When using imaging to identify NAFLD, a 1,000-step increase was associated with a 6% (95% CI: 6%-7%) lower risk. There was evidence for mediation by adiposity, accounting for 39% of the observed association. CONCLUSIONS Daily step count, a modifiable risk factor, is log-linearly and inversely associated with NAFLD. This association was only partially explained by adiposity. These findings from a large cohort study may have important implications for strategies to lower NAFLD risk.
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Affiliation(s)
- Evelynne S. Fulda
- Big Data Institute, Nuffield Department of Population Health, University of Oxford, Oxford, UNITED KINGDOM
| | - Laura Portas
- Big Data Institute, Nuffield Department of Population Health, University of Oxford, Oxford, UNITED KINGDOM
| | - Charlie Harper
- Big Data Institute, Nuffield Department of Population Health, University of Oxford, Oxford, UNITED KINGDOM
| | - David Preiss
- Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UNITED KINGDOM
| | - Derrick Bennett
- Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UNITED KINGDOM
| | - Aiden Doherty
- Big Data Institute, Nuffield Department of Population Health, University of Oxford, Oxford, UNITED KINGDOM
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21
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Chen C, Bu X, Deng L, Xia J, Wang X, Chen L, Li W, Huang J, Chen Q, Wang C. Astragaloside IV as a promising therapeutic agent for liver diseases: current landscape and future perspectives. Front Pharmacol 2025; 16:1574154. [PMID: 40337517 PMCID: PMC12055773 DOI: 10.3389/fphar.2025.1574154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Accepted: 04/10/2025] [Indexed: 05/09/2025] Open
Abstract
Astragaloside IV (C41H68O14, AS-IV) is a naturally occurring saponin isolated from the root of Astragalus membranaceus, a widely used traditional Chinese botanical drug in medicine. In recent years, AS-IV has attracted considerable attention for its hepatoprotective properties, which are attributed to its low toxicity as well as its anti-inflammatory, antioxidant and antitumour effects. Numerous preclinical studies have demonstrated its potential in the prevention and treatment of various liver diseases, including multifactorial liver injury, metabolic-associated fatty liver disease, liver fibrosis and liver cancer. Given the promising hepatoprotective potential of AS-IV and the growing interest in its research, this review provides a comprehensive summary of the current state of research on the hepatoprotective effects of AS-IV, based on literature available in databases such as CNKI, PubMed, ScienceDirect, Google Scholar and Web of Science. The hepatoprotective mechanisms of AS-IV are multifaceted, encompassing the inhibition of inflammatory responses, reduction of oxidative stress, improvement of insulin and leptin resistance, modulation of the gut microbiota, suppression of hepatocellular carcinoma cell proliferation and induction of tumour cell apoptosis. Notably, key molecular pathways involved in these effects include Nrf2/HO-1, NF-κB, NLRP3/Caspase-1, JNK/c-Jun/AP-1, PPARα/FSP1 and Akt/GSK-3β/β-catenin. Toxicity studies indicate that AS-IV has a high level of safety. In addition, this review discusses the sources, physicochemical properties, and current challenges in the development and clinical application of AS-IV, providing valuable insights into its potential as a hepatoprotective agent in the pharmaceutical and nutraceutical industries.
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Affiliation(s)
- Chunyan Chen
- School of Clinical Medical, Chengdu Medical College, Chengdu, China
- Department of Pharmacy, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Xiaolan Bu
- School of Clinical Medical, Chengdu Medical College, Chengdu, China
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Liping Deng
- School of Clinical Medical, Chengdu Medical College, Chengdu, China
- Department of Orthopedics, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Jiayan Xia
- School of Clinical Medical, Chengdu Medical College, Chengdu, China
- Department of Pediatrics, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Xinming Wang
- School of Clinical Medical, Chengdu Medical College, Chengdu, China
- Department of Pharmacy, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Li Chen
- School of Clinical Medical, Chengdu Medical College, Chengdu, China
- Department of Pharmacy, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Wen Li
- School of Clinical Medical, Chengdu Medical College, Chengdu, China
- Department of Pharmacy, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Jie Huang
- School of Clinical Medical, Chengdu Medical College, Chengdu, China
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Qixiang Chen
- School of Clinical Medical, Chengdu Medical College, Chengdu, China
- Department of Pharmacy, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Cheng Wang
- School of Clinical Medical, Chengdu Medical College, Chengdu, China
- Department of Pharmacy, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
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22
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Satari S, Mota INR, Silva ACL, Brito HO, Oliveira PA, Gil da Costa RM, Medeiros R. Hallmarks of Cancer Cachexia: Sexual Dimorphism in Related Pathways. Int J Mol Sci 2025; 26:3952. [PMID: 40362192 PMCID: PMC12071346 DOI: 10.3390/ijms26093952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 04/07/2025] [Accepted: 04/14/2025] [Indexed: 05/15/2025] Open
Abstract
Cancer-associated cachexia (CAC), also known as wasting syndrome, is a systemic condition that affects multiple tissues and organs via a variety of metabolic pathways. Systemic inflammation, progressive weight loss, depletion of adipose tissue, and skeletal muscle impairment are some of the hallmark features of cachexia. Despite various studies on the clinical features of CAC, the complexity of the syndrome continues to pose significant challenges in clinical practice, leading to late diagnoses and the absence of a standardised treatment. Men and women respond differently to CAC, which may be prompted by the pre-existing physiologic sex differences. This review presents the sexual dimorphism associated with the hallmark pathways involved in CAC. A comprehensive understanding of sexual dimorphism in these pathways could drive research on cachexia to prioritise the inclusion of more females in related studies in order to achieve personalised sex-based therapeutic approaches and, consequently, enhance treatment efficacy and better patient outcomes.
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Affiliation(s)
- Setareh Satari
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Pathology and Laboratory Medicine Dep./Clinical Pathology, Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC Raquel Seruca), 4200-072 Porto, Portugal; (S.S.); (I.N.R.M.); (A.C.L.S.); (R.M.G.d.C.)
- Faculty of Medicine, University of Porto (FMUP), 4200-319 Porto, Portugal
- The Institute of Public Health, University of Porto (ISPUP), Rua das Taipas 135, 4050-600 Porto, Portugal
| | - Inês N. R. Mota
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Pathology and Laboratory Medicine Dep./Clinical Pathology, Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC Raquel Seruca), 4200-072 Porto, Portugal; (S.S.); (I.N.R.M.); (A.C.L.S.); (R.M.G.d.C.)
- Faculty of Sciences, University of Porto (FCUP), 4169-007 Porto, Portugal
| | - Ana Carolina Leão Silva
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Pathology and Laboratory Medicine Dep./Clinical Pathology, Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC Raquel Seruca), 4200-072 Porto, Portugal; (S.S.); (I.N.R.M.); (A.C.L.S.); (R.M.G.d.C.)
- Faculty of Medicine, University of Porto (FMUP), 4200-319 Porto, Portugal
| | - Haissa Oliveira Brito
- Research Center For Experimental and Clinical Physiology and Pharmacology (NEC)/Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB)/Bioanalysis Lab (LaBIO), Federal University of Maranhão (UFMA), São Luís 65080-805, Brazil;
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), Inov4Agro, University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal;
| | - Paula A. Oliveira
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), Inov4Agro, University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal;
| | - Rui Miguel Gil da Costa
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Pathology and Laboratory Medicine Dep./Clinical Pathology, Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC Raquel Seruca), 4200-072 Porto, Portugal; (S.S.); (I.N.R.M.); (A.C.L.S.); (R.M.G.d.C.)
- Research Center For Experimental and Clinical Physiology and Pharmacology (NEC)/Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB)/Bioanalysis Lab (LaBIO), Federal University of Maranhão (UFMA), São Luís 65080-805, Brazil;
- Laboratory for Process Engineering, Environment, Biotechnology and Energy (LEPABE), Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Pathology and Laboratory Medicine Dep./Clinical Pathology, Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC Raquel Seruca), 4200-072 Porto, Portugal; (S.S.); (I.N.R.M.); (A.C.L.S.); (R.M.G.d.C.)
- Faculty of Medicine, University of Porto (FMUP), 4200-319 Porto, Portugal
- ICBAS-School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal
- Biomedical Research Center, Faculty of Health Sciences of the Fernando Pessoa University, 4249-004 Porto, Portugal
- ECO-European Cancer Organization, 1040 Brussels, Belgium
- Research Department of the Portuguese League Against Cancer—Regional Nucleus of the North (Liga Portuguesa Contra o Cancro—Núcleo Regional do Norte), 4200-172 Porto, Portugal
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Wu F, Zheng F, Li X, Wu D, Li H, Zeng Y, Tang Y, Liu S, Li A. Association between non-skimmed milk consumption and metabolic dysfunction-associated fatty liver disease in US adults: insights from NHANES data. BMC Gastroenterol 2025; 25:270. [PMID: 40251472 PMCID: PMC12007357 DOI: 10.1186/s12876-025-03834-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Accepted: 04/01/2025] [Indexed: 04/20/2025] Open
Abstract
PURPOSE Previous studies on the association between non-skimmed milk consumption and non-alcoholic fatty liver disease (NAFLD) have reported inconsistent findings, with some suggesting an increased risk and others indicating a protective effect. Moreover, as the research focus has shifted globally from NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD), there remains limited evidence on the relationship between non-skimmed milk consumption and MAFLD. The objective of this cross-sectional study was to investigate this association using data from the National Health and Nutrition Examination Survey (NHANES). METHODS In this U.S. population-based study, adults with complete information on non-skimmed milk consumption and MAFLD diagnosis from the 2017-March 2020 Pre-Pandemic NHANES were included. MAFLD was defined using the controlled attenuation parameter (CAP). The association between non-skimmed milk consumption and MAFLD was assessed using weighted multivariable logistic regression, adjusting for potential confounders. Subgroup and sensitivity analyses were conducted to evaluate effect modifications and robustness. RESULTS The study involved 3,758 participants in total, 1,423 (37.87%) of whom had MAFLD according to the diagnosis. Frequent non-skimmed milk consumption was independently associated with higher MAFLD risk. Compared to the "Rarely" group (< 1 time/week), the "Sometimes" group (≥ 1 time/week but < 1 time/day) had an odds ratio (OR) of 1.67 (95% CI: 1.32-2.12, P = 0.004), and the "Often" group (≥ 1 time/day) had an OR of 1.36 (95% CI: 1.06-1.75, P = 0.046). Stratified analysis revealed that the association was significantly modified by education level (P for interaction = 0.010), with a stronger association observed among participants with higher education levels. Sensitivity analysis yielded consistent results, further supporting the robustness of the association. CONCLUSION Our findings suggest a significant association between frequent non-skimmed milk consumption and risk of MAFLD, particularly in highly educated individuals. These results highlight the importance of dietary modifications, specifically reducing non-skimmed milk intake, as a potential preventive strategy for MAFLD, especially in high-risk populations.
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Affiliation(s)
- Futao Wu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fuying Zheng
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xue Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Danzhu Wu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Honghao Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Gastroenterology, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, China
| | - Yingyi Zeng
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yan Tang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Side Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
- Department of Gastroenterology, Zhuhai Peoples Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China.
| | - Aimin Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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24
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Taweesap P, Potue P, Khamseekaew J, Iampanichakul M, Jan-O B, Pakdeechote P, Maneesai P. Luteolin Relieves Metabolic Dysfunction-Associated Fatty Liver Disease Caused by a High-Fat Diet in Rats Through Modulating the AdipoR1/AMPK/PPARγ Signaling Pathway. Int J Mol Sci 2025; 26:3804. [PMID: 40332475 PMCID: PMC12028338 DOI: 10.3390/ijms26083804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Revised: 04/11/2025] [Accepted: 04/15/2025] [Indexed: 05/08/2025] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a significant global public health issue. Luteolin possesses several beneficial biological properties, including antioxidation and anti-inflammation. This study investigated luteolin's effect and potential mechanisms on MAFLD in high-fat diet (HFD)-fed rats. Rats were administered an HFD supplemented with fructose for 12 weeks to induce MAFLD. After that, the HFD-fed rats were given either luteolin (50 or 100 mg/kg/day) or metformin (100 mg/kg/day) for 4 weeks. Luteolin improved metabolic parameters induced by the HFD, since it decreased body weight, blood pressure, fasting blood glucose, serum insulin, free fatty acids, cholesterol, and triglyceride levels (p < 0.05). Luteolin reduced hepatic injury and inflammatory markers in HFD-fed rats (p < 0.05). Additionally, HFD-fed rats treated with luteolin showed reduced malondialdehyde and raised catalase activity in plasma (p < 0.05). Luteolin attenuated hepatic steatosis compared to the untreated rats (p < 0.05). Luteolin also increased plasma adiponectin levels accompanied by upregulation of adiponectin receptor 1 (AdipoR1), AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor γ (PPAR-γ) protein expression in liver (p < 0.05). These findings revealed that luteolin ameliorated HFD-induced MAFLD in rats, possibly by reducing metabolic alterations and oxidative stress and restoring AdipoR1, AMPK, and PPARγ protein expression in HFD-fed rats.
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Affiliation(s)
| | | | | | | | | | | | - Putcharawipa Maneesai
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.T.); (P.P.); (J.K.); (M.I.); (B.J.-O.); (P.P.)
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25
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Pădureanu V, Dop D, Radu L, Rădulescu D, Pădureanu R, Pîrșcoveanu DFV, Caragea DC. Nephrological, Pulmonary, and Dermatological Complications in the Context of MAFLD/NAFLD: A Narrative Review. Metabolites 2025; 15:272. [PMID: 40278401 PMCID: PMC12029749 DOI: 10.3390/metabo15040272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 04/07/2025] [Accepted: 04/11/2025] [Indexed: 04/26/2025] Open
Abstract
Background: The most common cause of chronic liver disease is now known to be non-alcoholic fatty liver disease (NAFLD), recently redefined as metabolic-associated fatty liver disease (MAFLD). This review aims to synthesize current evidence on the pathophysiology and clinical implications of nephrological, pulmonary, and dermatological manifestations among NAFLD/MAFLD patients. In order to find safe and efficient treatments, NAFLD/MAFLD has emerged as a primary concern for hepatologists worldwide. Methods: We conducted a comprehensive review of the literature from major databases, focusing on studies that evaluated the extrahepatic manifestations of NAFLD/MAFLD. Emphasis was placed on identifying pathophysiological mechanisms and assessing their clinical impact on renal, pulmonary, and dermatological systems. Results: Recent developments in the management of chronic viral hepatitis have lowered the mortality rate associated with chronic liver disease. However, the prevalence of NAFLD/MAFLD continues to rise, making chronic liver disease a significant health concern for the future. An increasing percentage of patients on liver transplant waiting lists now have cirrhosis and hepatocellular carcinoma due to non-alcoholic liver disease. Furthermore, the incidence and prevalence of chronic kidney disease have surged, linking NAFLD/MAFLD to higher morbidity, mortality, and healthcare costs. Conclusions: NAFLD/MAFLD is underdiagnosed and underappreciated, yet its incidence is rapidly increasing, raising concerns about a potential global epidemic. Given its multisystemic impact-extending to renal, pulmonary, and dermatological complications-it is crucial to develop interdisciplinary strategies for early detection and effective management of the disease.
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Affiliation(s)
- Vlad Pădureanu
- Department of Internal Medicine, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania;
| | - Dalia Dop
- Department of Pediatrics, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania;
| | - Lucrețiu Radu
- Department of Hygiene, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania;
| | - Dumitru Rădulescu
- Department of Surgery, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania
| | - Rodica Pădureanu
- Department of Internal Medicine, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania;
| | | | - Daniel Cosmin Caragea
- Department of Nephrology, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania;
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26
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Miao Z, Zhang X, Xu Y, Liu Y, Yang Q. Unveiling the nexus: pyroptosis and its crucial implications in liver diseases. Mol Cell Biochem 2025; 480:2159-2176. [PMID: 39477911 DOI: 10.1007/s11010-024-05147-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 10/22/2024] [Indexed: 04/02/2025]
Abstract
Pyroptosis, a distinctive form of programmed cell death orchestrated by gasdermin proteins, manifests as cellular rupture, accompanied by the release of inflammatory factors. While pyroptosis is integral to anti-infection immunity, its aberrant activation has been implicated in tumorigenesis. The liver, as the body's largest metabolic organ, is rich in various enzymes and governs metabolism. It is also the primary site for protein synthesis. Recent years have witnessed the emergence of pyroptosis as a significant player in the pathogenesis of specific liver diseases, exerting a pivotal role in both physiological and pathological processes. A comprehensive exploration of pyroptosis can unveil its contributions to the development and regression of conditions such as hepatitis, cirrhosis, and hepatocellular carcinoma, offering innovative perspectives for clinical prevention and treatment. This review consolidates current knowledge on key molecules involved in cellular pyroptosis and delineates their roles in liver diseases. Furthermore, we discuss the potential of leveraging pyroptosis as a novel or existing anti-cancer strategy.
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Affiliation(s)
- Zeyu Miao
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Xiaorong Zhang
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Yang Xu
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Yan Liu
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Qing Yang
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin Province, China.
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27
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Mikołajczyk-Stecyna J, Zuk E, Chmurzynska A, Blatkiewicz M, Jopek K, Rucinski M. Exposure to a choline-deficient diet during pregnancy and lactation alters the liver transcriptome profile in offspring of dams with fatty liver. Clin Nutr ESPEN 2025; 66:9-23. [PMID: 39800134 DOI: 10.1016/j.clnesp.2025.01.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/11/2024] [Accepted: 01/02/2025] [Indexed: 01/15/2025]
Abstract
BACKGROUND & AIMS The developmental origin of health and disease hypothesis shows that early adverse exposures can have lifelong health effects. Thus, the aim of this study was to analyze the impact of choline intake during pregnancy and/or lactation on gene expression profiles in the liver of 24-day-old male rat offspring from dams with non-alcoholic fatty liver disease (NAFLD). METHODS Phenotypic characteristic, histological examination and global transcriptome pattern of liver tissue specimens obtained from offspring of dams suffering from fatty liver, provided with proper choline intake during pregnancy and lactation (NN), fed a choline-deficient diet during both periods (DD), deprived of choline only during pregnancy (DN), or only during lactation (ND), was performed. The global gene expression profile was analyzed by using microarray approach (Affymetrix® Rat Gene 2.1 ST Array Strip). The relative expression of selected genes was validated by real-time polymerase chain reaction (qPCR). RESULTS The histological examination of rat liver sections indicated alternations typical for fatty liver in all analyzed groups with increased progression among groups deprived of choline. Choline deficiency in the maternal diet was associated with changes in body mass and composition but not with biochemical marker levels, except for the high density lipoprotein fraction of cholesterol (HDL). Enhanced expression of genes involved in oxidative stress, cell proliferation, activation of catabolic processes related to hepatocyte dysfunction and cell membrane composition were simultaneously observed in all choline-deficient groups. CONCLUSIONS An adequate amount of choline in the diet of a mother with fatty liver during pregnancy and/or lactation can regulate gene expression in the offspring's liver and contribute to a milder stage of the disease in the progeny. Moreover, proper choline supply during the postpartum period is as crucial as during the prenatal period.
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Affiliation(s)
- Joanna Mikołajczyk-Stecyna
- Poznań University of Life Sciences, Department of Human Nutrition and Dietetics, Wojska Polskiego 31, 60-624 Poznań, Poland.
| | - Ewelina Zuk
- Poznań University of Life Sciences, Department of Human Nutrition and Dietetics, Wojska Polskiego 31, 60-624 Poznań, Poland
| | - Agata Chmurzynska
- Poznań University of Life Sciences, Department of Human Nutrition and Dietetics, Wojska Polskiego 31, 60-624 Poznań, Poland
| | | | - Karol Jopek
- University of Medical Sciences, Department of Histology and Embryology, Poznań, Poland
| | - Marcin Rucinski
- University of Medical Sciences, Department of Histology and Embryology, Poznań, Poland
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Xiong W, Li J, Tian A, Mao X. Unravelling the Role of PANoptosis in Liver Diseases: Mechanisms and Therapeutic Implications. Liver Int 2025; 45:e70000. [PMID: 40116786 DOI: 10.1111/liv.70000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 12/28/2024] [Accepted: 01/08/2025] [Indexed: 03/23/2025]
Abstract
PANoptosis is a multimodal form of cell death that involves inflammatory, apoptotic, and necroptotic pathways, playing a key role in the development of liver diseases. This article first outlines the definition and characteristics of PANoptosis, and then explores its mechanisms of action in different types of liver diseases, including acute liver injury, liver failure, metabolic dysfunction-associated fatty liver disease, and hepatocellular carcinoma. Furthermore, this article analyses the molecular regulatory network of PANoptosis and potential therapeutic targets. Finally, this article summarises the current research on PANoptosis in liver diseases and future research directions, and it reviews the role of the emerging cell death mechanism of PANoptosis in liver diseases.
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Affiliation(s)
- Wanyuan Xiong
- The First Clinical Medical College of Lanzhou University, Lanzhou University, Lanzhou, Gansu, China
- Department of Infectious Disease, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Junfeng Li
- The First Clinical Medical College of Lanzhou University, Lanzhou University, Lanzhou, Gansu, China
- Department of Infectious Disease, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
- Department of Liver Disease, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Aiping Tian
- Department of Infectious Disease, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Xiaorong Mao
- Department of Infectious Disease, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
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Potter KJ, Phinney J, Kulai T, Munro V. Effects of GLP-1 receptor agonist therapy on resolution of steatohepatitis in non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Can Assoc Gastroenterol 2025; 8:47-57. [PMID: 40224572 PMCID: PMC11991874 DOI: 10.1093/jcag/gwae057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/15/2025] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is common, can progress to cirrhosis and hepatic decompensation, and has no approved medical therapy in Canada. Objective We conducted a systematic review on whether glucagon-like peptide-1 receptor agonists (GLP-1RA) improve non-alcoholic steatohepatitis (NASH) compared to standard care in NAFLD. Methods We searched Medline Ovid, EMBASE(Elsevier), Cochrane CENTRAL, Clinical Trials.gov, and the World Health Organization International Clinical Trials Registry Platform in November 2023 for randomized controlled trials. Inclusion criteria included patients ≥13 years with NAFLD receiving GLP-1RA for ≥6 months compared to standard care/placebo. Cochrane risk-of-bias 2.0 tool was used for each outcome. After screening results in duplicate, we performed meta-analysis and reported odds ratios (OR) for dichotomous and mean difference of change score for continuous outcomes. Results Six studies with 478 patients met inclusion criteria; 3 studies reported on the primary endpoint resolution of NASH. GLP-1RA likely leads to resolution of NASH (OR 4.45 (95% CI 1.92, 10.3)) and reduction in liver steatosis on imaging (-5.09% (95% CI -7.49, -2.69), but little to no reduction in liver stiffness on imaging (mean difference -0.17 kPa (95% CI -0.34, 0)). Interpretation Treatment with GLP-1RA in NAFLD patients for ≥6 months can probably lead to improvement in NASH on liver biopsy and reduce liver steatosis on imaging. Whether improvements in steatosis on biopsy or imaging results in clinically significant outcomes need to be elucidated as the effects of GLP-1RA on liver fibrosis are unclear; larger ongoing trials may provide more definitive answers. Protocol Registration: PROSPERO-CRD42023472186.
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Affiliation(s)
- Kathryn J Potter
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4Z5, Canada
| | - Jackie Phinney
- Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, NB, E2L 4L5, Canada
| | - Tasha Kulai
- Division of Digestive Care and Endoscopy, Dalhousie University, Halifax, NS, B3H 2Y9, Canada
| | - Vicki Munro
- Division of Endocrinology, Dalhousie University, Halifax, NS, B3H 2Y9, Canada
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Stamation R. Endogenous Ethanol Production in the Human Alimentary Tract: A Literature Review. J Gastroenterol Hepatol 2025; 40:783-790. [PMID: 39853762 PMCID: PMC11968154 DOI: 10.1111/jgh.16869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 11/28/2024] [Accepted: 12/22/2024] [Indexed: 01/26/2025]
Abstract
Endogenous ethanol production, or auto-brewery syndrome (ABS), is a rare condition of the human alimentary canal that results in intoxication without alcohol consumption. Despite its clinical significance, ABS remains largely undiagnosed because of a lack of awareness among clinicians. Published cases have reported extensive biopsychosocial comorbidities accompanying delayed diagnosis and incomplete management; these include social rejection and family separation, court-ordered alcohol rehabilitation and psychiatric admission, legal and employment ramifications, and deteriorating mental health and suicidality. In this mini review, we aim to educate and enlighten clinicians by discussing literature findings pertaining to the pathophysiological mechanisms of gut dysbiosis due to overgrowth of Saccharomyces cerevisiae, E. coli and Klebsiella, impaired intestinal barrier function, and dysregulation of the hypothalamic-pituitary-adrenal axis. Furthermore, we discuss recently discovered associations with sleep quality and mood disorders and explore the medical sequelae of metabolic dysfunction-associated fatty liver disease and metabolic dysfunction-associated steatohepatitis. Drawing on these data, we propose protocols for initial care in the emergency room, subsequent critical care, diagnostic testing with glucose challenge testing, and definitive microbiological testing during the acute phase of illness. We also present an empirical treatment outline while awaiting confirmation of causative organisms and sensitivities.
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Affiliation(s)
- Renee Stamation
- Department of Rural HealthUniversity of Melbourne, Echuca Clinical SchoolEchucaVictoriaAustralia
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Wang P, Song D, Han J, Zhang J, Chen H, Gao R, Shen H, Li J. Comparing Three Ultrasound-Based Techniques for Diagnosing and Grading Hepatic Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease. Acad Radiol 2025; 32:1949-1957. [PMID: 39294051 DOI: 10.1016/j.acra.2024.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 08/25/2024] [Accepted: 09/01/2024] [Indexed: 09/20/2024]
Abstract
RATIONALE AND OBJECTIVES To compare the diagnostic accuracy and grading ability of ultrasound-derived fat fraction (UDFF), controlled attenuation parameters (CAP), and hepatic/renal ratio (HRR) for hepatic steatosis in metabolic dysfunction-associated steatotic liver disease (MASLD) using magnetic resonance imaging proton density fat fraction (PDFF) as the gold standard. METHODS Patients suspected of having MASLD in our hospital between October 2023 and May 2024 were divided into the MASLD group and the control group. All patients underwent UDFF, CAP, and PDFF examinations. HRR was measured during routine ultrasound examination. In statistical analysis, we initially assessed the correlation between UDFF, CAP, HRR, and general characteristics of subjects with PDFF. Subsequently, receiver operating characteristic curve were employed to evaluate and compare the diagnostic performance of UDFF, CAP, and HRR for different grades of hepatic steatosis in MASLD. Their area under the curve, optimal cut-off value, sensitivity, and specificity were also determined. Finally, predictive factors determined hepatic steatosis in MASLD (PDFF≥6%) were identified through binary logistic regression analysis. RESULTS 115 individuals were ultimately included in the MASLD group, while 102 were included in the control group. UDFF, CAP, and HRR were all positively correlated with PDFF. Among them, UDFF exhibited the strongest correlation with PDFF (ρ = 0.91). Furthermore, in the comparison of diagnostic efficacy among different grades of hepatic steatosis, UDFF outperformed CAP and HRR (p < 0.05). However, there were no statistically significant differences in AUCs between CAP and HRR across all three grades. The AUCs for UDFF in ≥S1, ≥S2, and ≥S3 were 0.99 (95% CI 0.97 to 1.00), 0.96 (95% CI 0.93 to 0.98), and 0.97 (95% CI 0.94 to 0.99), respectively. The optimal thresholds for UDFF are determined as follows: ≥ 6% for grade S1; ≥ 15% for grade S2; and ≥ 23% for grade S3. Multivariate analysis revealed that only age, UDFF, and CAP were important influencing factors for hepatic steatosis in MASLD. CONCLUSION The diagnostic accuracy of UDFF surpassed that of CAP and HRR in the detection and grading of hepatic steatosis in MASLD.
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Affiliation(s)
- Pingping Wang
- Southeast University Zhongda Hospital, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing, China
| | - Danlei Song
- Southeast University Zhongda Hospital, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing, China
| | - JiaHao Han
- Southeast University Zhongda Hospital, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing, China
| | - Jing Zhang
- Southeast University Zhongda Hospital, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing, China
| | - Huihui Chen
- Southeast University Zhongda Hospital, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing, China
| | - Ruixia Gao
- Southeast University Zhongda Hospital, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing, China
| | - Huiming Shen
- Southeast University Zhongda Hospital, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing, China
| | - Jia Li
- Southeast University Zhongda Hospital, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing, China.
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Guo W, Weng T, Song Y. Association of serum iron status with MASLD and liver fibrosis. PLoS One 2025; 20:e0319057. [PMID: 40168317 PMCID: PMC11960921 DOI: 10.1371/journal.pone.0319057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 01/27/2025] [Indexed: 04/03/2025] Open
Abstract
BACKGROUND The MASLD proposal updates and supplements the previous definition of NAFLD, making it more suitable for addressing the current understanding of chronic liver diseases. This study aims to investigate the potential association between serum iron status and the occurrence of MASLD and liver fibrosis. METHODS An in-depth analysis was conducted using the 2017-2020 NHANES data. To assess the relationship between serum iron status and the prevalence of MASLD and liver fibrosis, we performed comprehensive data analysis. This approach accounts for multiple variables, enhancing the robustness and reliability of our results by reducing potential confounding factors. RESULTS Our application of linear regression models provided significant insights through a comprehensive data analysis. Elevated serum ferritin, TIBC, and UIBC showed a distinct positive correlation with CAP, while only serum ferritin was positively correlated with LSM. Multivariate logistic regression analysis revealed that elevated levels of serum ferritin, TIBC, and UIBC were significantly associated with the occurrence of MASLD, whereas only serum ferritin showed a similar association with the occurrence of liver fibrosis. CONCLUSION This study highlights the significant positive correlation between elevated levels of serum ferritin, TIBC, and UIBC with CAP and the prevalence of MASLD. A similar relationship was observed between serum ferritin with LSM and the prevalence of liver fibrosis.
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Affiliation(s)
- Wenying Guo
- Ningbo medical center Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, People’s Republic of China
| | - Ting Weng
- Ningbo medical center Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, People’s Republic of China
| | - Yufei Song
- Ningbo medical center Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, People’s Republic of China
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Ververeli CL, Dimitroglou Y, Soulaidopoulos S, Cholongitas E, Aggeli C, Tsioufis K, Tousoulis D. Cardiac Remodeling and Arrhythmic Burden in Pre-Transplant Cirrhotic Patients: Pathophysiological Mechanisms and Management Strategies. Biomedicines 2025; 13:812. [PMID: 40299454 PMCID: PMC12025098 DOI: 10.3390/biomedicines13040812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Revised: 03/22/2025] [Accepted: 03/25/2025] [Indexed: 04/30/2025] Open
Abstract
Background: Chronic liver disease (CLD) and cirrhosis contribute to approximately 2 million deaths annually, with primary causes including alcohol-related liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and chronic hepatitis B and C infections. Among these, MASLD has emerged as a significant global health concern, closely linked to metabolic disorders and a leading cause of liver failure and transplantation. Objective: This review aims to highlight the interplay between cirrhosis and cardiac dysfunction, emphasizing the pathophysiology, diagnostic criteria, and management of cirrhotic cardiomyopathy (CCM). Methods: A comprehensive literature review was conducted to evaluate the hemodynamic and structural cardiac alterations in cirrhosis. Results: Cirrhosis leads to portal hypertension and systemic inflammation, contributing to CCM, which manifests as subclinical cardiac dysfunction, impaired contractility, and electrophysiological abnormalities. Structural changes, such as increased left ventricular mass, myocardial fibrosis, and ion channel dysfunction, further impair cardiac function. Vasodilation in the splanchnic circulation reduces peripheral resistance, triggering compensatory tachycardia, while the activation of the renin-angiotensin-aldosterone system (RAAS) promotes fluid retention and increases cardiac preload. Chronic inflammation and endotoxemia exacerbate myocardial dysfunction. The 2005 World Congress of Gastroenterology (WCG) and the 2019 Cirrhotic Cardiomyopathy Consortium (CCC) criteria provide updated diagnostic frameworks that incorporate global longitudinal strain (GLS) and tissue Doppler imaging (TDI). Prolonged QT intervals and arrhythmias are frequently observed. Managing heart failure in cirrhotic patients remains complex due to intolerance to afterload-reducing agents, and beta-blockers require careful use due to potential systemic hypotension. The interaction between CCM and major interventions, such as transjugular intrahepatic portosystemic shunt (TIPS) and orthotopic liver transplantation (OLT), highlights the critical need for thorough preoperative cardiac evaluation and vigilant postoperative monitoring. Conclusions: CCM is a frequently underdiagnosed yet significant complication of cirrhosis, impacting prognosis, particularly post-liver transplantation. Early identification using echocardiography and thorough evaluations of arrhythmia risk in cirrhotic patients are critical for optimizing management strategies. Future research should focus on targeted therapeutic approaches to mitigate the cardiac burden in cirrhotic patients and improve clinical outcomes.
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Affiliation(s)
- Charilila-Loukia Ververeli
- 1st Department of Cardiology, Hippokrateio General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.-L.V.); (S.S.); (C.A.); (K.T.); (D.T.)
| | - Yannis Dimitroglou
- 1st Department of Cardiology, Hippokrateio General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.-L.V.); (S.S.); (C.A.); (K.T.); (D.T.)
| | - Stergios Soulaidopoulos
- 1st Department of Cardiology, Hippokrateio General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.-L.V.); (S.S.); (C.A.); (K.T.); (D.T.)
| | - Evangelos Cholongitas
- 1st Department of Internal Medicine, Laiko General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Constantina Aggeli
- 1st Department of Cardiology, Hippokrateio General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.-L.V.); (S.S.); (C.A.); (K.T.); (D.T.)
| | - Konstantinos Tsioufis
- 1st Department of Cardiology, Hippokrateio General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.-L.V.); (S.S.); (C.A.); (K.T.); (D.T.)
| | - Dimitris Tousoulis
- 1st Department of Cardiology, Hippokrateio General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.-L.V.); (S.S.); (C.A.); (K.T.); (D.T.)
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Dai JJ, Deng Y, Wang GF, Lin KQ, He JR, Hu XG. Relationship of serum 25(OH)D3 and PTX3 with liver fat content in patients with non-alcoholic fatty liver disease: Diagnostic value for liver fibrosis. Shijie Huaren Xiaohua Zazhi 2025; 33:192-198. [DOI: 10.11569/wcjd.v33.i3.192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Revised: 02/15/2025] [Accepted: 03/16/2025] [Indexed: 03/28/2025] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in China. Vitamin D and pentraxin 3 (PTX3) participate in the occurrence and development of NAFLD by regulating calcium and phosphorus metabolism and inflammation. This study analyzed the relationship of serum 25-hydroxy vitamin D3 [25(OH)D3] and PTX3 levels with liver fat content and liver fibrosis in patients with NAFLD.
AIM To analyze the relationship of serum 25(OH)D3 and PTX3 with liver fat content in patients with NAFLD, as well as their diagnostic value for liver fibrosis.
METHODS A total of 120 NAFLD patients in our hospital from June 2022 to September 2023 were selected as a study group, and another 120 healthy individuals in the same period were selected as a control group. General information and serum levels of 25(OH)D3 and PTX3 were compared between and two groups, and the levels of 25(OH)D3 and PTX3 were compared in patients with different liver fat contents in the study group. The correlation between serum levels of 25(OH)D3 and PTX3 and liver fat content in NAFLD patients was analyzed. The levels of serum 25(OH)D3, PTX3, liver fibrosis, and liver function indicators [hyaluronic acid (HA), procollagen type Ⅲ (PCⅢ), procollagen type Ⅳ (PCIV), alanine aminotransferase (ALT), and aspartate aminotransferase (AST)] were compared among patients with different degrees of liver fibrosis in the study group. The correlation of serum 25(OH)D3 and PTX3 levels with liver fibrosis and liver function indicators was examined, and their value for diagnosing liver fibrosis was assessed.
RESULTS Serum 25(OH)D3 level in the study group was lower than that of the control group, while PTX3 level was higher than that of the control group (P < 0.05). There was a statistically significant difference in serum 25(OH)D3 and PTX3 levels among patients with different liver fat contents in the study group (P < 0.05). As the liver fat content increased, serum 25(OH)D3 levels significantly decreased, while PTX3 levels significantly increased. Serum 25(OH)D3 levels were negatively correlated with liver fat content in NAFLD patients, while PTX3 levels were positively correlated with liver fat content in NAFLD patients (P < 0.05). Serum 25(OH)D3 levels in patients at risk of liver fibrosis in the study group were lower than those in patients without liver fibrosis, while the levels of PTX3, HA, PC Ⅲ, PC Ⅳ, ALT, and AST were higher than those of patients without liver fibrosis (P < 0.05). Serum 25(OH)D3 levels in NAFLD patients were negatively correlated with HA, PC Ⅲ, PC Ⅳ, ALT, and AST levels, while PTX3 levels were positively correlated with HA, PC Ⅲ, PC Ⅳ, ALT, and AST levels (P < 0.05). The area under the curve (AUC) of serum 25(OH)D3 and PTX3 alone for diagnosing liver fibrosis in patients with NAFLD was 0.713 and 0.781, respectively, while the AUC of their combination was 0.908, which was greater than the AUC of either of them alone (P < 0.05).
CONCLUSION Serum 25(OH)D3 level in NAFLD patients is negatively correlated with liver fat content, while serum PTX3 level is positively correlated with liver fat content. The two have appreciated diagnostic value in liver fibrosis.
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Affiliation(s)
- Jian-Ji Dai
- Department of Oncology and Vascular Intervention, Jinhua Central Hospital, Jinhua 321000, Zhejiang Province, China
| | - Yi Deng
- Department of Oncology and Vascular Intervention, Jinhua Central Hospital, Jinhua 321000, Zhejiang Province, China
| | - Guo-Feng Wang
- Department of Oncology and Vascular Intervention, Jinhua Central Hospital, Jinhua 321000, Zhejiang Province, China
| | - Kai-Qin Lin
- Department of Oncology and Vascular Intervention, Jinhua Central Hospital, Jinhua 321000, Zhejiang Province, China
| | - Jian-Rong He
- Department of Oncology and Vascular Intervention, Jinhua Central Hospital, Jinhua 321000, Zhejiang Province, China
| | - Xiao-Gang Hu
- Department of Oncology and Vascular Intervention, Jinhua Central Hospital, Jinhua 321000, Zhejiang Province, China
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Jain P, Jain A, Deshmukh R, Samal P, Satapathy T, Ajazuddin. Metabolic dysfunction-associated steatotic liver disease (MASLD): Exploring systemic impacts and innovative therapies. Clin Res Hepatol Gastroenterol 2025; 49:102584. [PMID: 40157567 DOI: 10.1016/j.clinre.2025.102584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Revised: 03/24/2025] [Accepted: 03/27/2025] [Indexed: 04/01/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), which includes the inflammatory subtype metabolic dysfunction-associated steatohepatitis, is a prominent cause of chronic liver disease with systemic effects. Insulin resistance, obesity, and dyslipidaemia produce MASLD in over 30 % of adults. It is a global health issue. From MASLD to MASH, hepatic inflammation and fibrosis grow, leading to cirrhosis, hepatocellular cancer, and extrahepatic complications such CVD, CKD, and sarcopenia. Effects of MASLD to MASH are mediated through mechanisms that include inflammation, oxidative stress, dysbiosis, and predisposition through genetic makeup. Advances in diagnostic nomenclature in the past few years have moved the emphasis away from NAFLD to MASLD, focusing on the metabolic etiology and away from the stigma of an alcoholic-related condition. Epidemiological data show a large geographical variability and increasing prevalence in younger populations, particularly in regions with high carbohydrate-rich diets and central adiposity. Lifestyle modification is considered as the main management of MASLD currently. This may include dietary intervention, exercise, and weight loss management. Pharmaceutical management is primarily aimed at metabolic dysfunction with promising findings for GLP-1 receptor agonists, pioglitazone and SGLT-2 inhibitors, which can correct both hepatic and systemic outcome. However, it still depends on well-integrated multidisciplinary care models by considering complex relationships between MASLD and its effects on extrahepatic organs. Determining complications at an early stage; developing precision medicine strategies; exploring new therapeutic targets will represent crucial factors in improving their outcomes. This review discuss the systemic nature of MASLD and calls for multiple collaborations to reduce its far-reaching health impacts and our quest for understanding its pathological mechanisms. Thus, collective efforts that are required to address MASLD are under the public health, clinical care, and research angles toward effectively containing its rapidly increasing burden.
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Affiliation(s)
- Parag Jain
- Department of Pharmacology, Rungta College of Pharmaceutical Sciences and Research, Bhilai, C.G., India, 490024.
| | - Akanksha Jain
- Department of Biotechnology, Bharti University, Durg, C.G., India
| | - Rohitas Deshmukh
- Institute of Pharmaceutical Research, GLA University, Mathura, India, 281406
| | - Pradeep Samal
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya, Bilaspur, C.G., India
| | - Trilochan Satapathy
- Department of Pharmacy, Columbia Institute of Pharmaceutical Sciences, Raipur, C.G., India, 493111
| | - Ajazuddin
- Department of Pharmacology, Rungta College of Pharmaceutical Sciences and Research, Bhilai, C.G., India, 490024
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Liao X, Yu S, Wang L, Zhang R, Yu K. Elevated red blood cell folate levels are associated with metabolic dysfunction-associated steatotic liver disease: results from NHANES 2017-2020. Front Physiol 2025; 16:1494863. [PMID: 40182691 PMCID: PMC11965589 DOI: 10.3389/fphys.2025.1494863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 02/28/2025] [Indexed: 04/05/2025] Open
Abstract
Introduction Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide. However, the role of folate in MASLD remains controversial. This study aimed to investigate the association between two folate indicators [serum folate and red blood cell (RBC) folate] and MASLD prevalence using data from the 2017-2020 National Health and Nutrition Examination Survey (NHANES). Methods A total of 3,879 participants without liver disease or significant alcohol consumption were included in the final analysis. Hepatic steatosis was assessed via transient elastography, with MASLD defined as a controlled attenuation parameter (CAP) ≥285 dB/m and the presence of at least one cardiometabolic risk factor. Logistic regression and generalized additive models (GAMs) were used to evaluate associations between folate levels and MASLD, with subgroup analyses stratified by age, gender, and body mass index (BMI). Results After full adjustment for confounders, RBC folate exhibited a significant positive association with MASLD (OR = 1.111 and 95% CI: 1.015-1.216 per 1-unit increase). In contrast, serum folate showed a transient negative association in minimally adjusted models (OR = 0.869 and 95% CI: 0.802-0.941), which disappeared after further adjustments. Subgroup analyses confirmed that age, gender, and BMI did not modify the RBC folate-MASLD relationship. Discussion These findings suggest that elevated RBC folate levels are independently associated with MASLD prevalence, whereas serum folate may lack clinical relevance due to susceptibility to confounding factors. RBC folate, as a stable biomarker of long-term folate status, may serve as a superior indicator for investigating folate-MASLD associations.
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Affiliation(s)
- Xin Liao
- Department of General Medicine, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
| | - Song Yu
- Department of General Medicine, the Third Affiliated Hospital of Chengdu Medical College, Chengdu Pidu District People’s Hospital, Chengdu, Sichuan, China
| | - Lin Wang
- Department of General Medicine, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
| | - Ruyue Zhang
- Department of General Medicine, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
| | - Ke Yu
- Department of General Medicine, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
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Hall MG, Cashmore M, Cho HM, Ittermann B, Keenan KE, Kolbitsch C, Lee C, Li C, Ntata A, Obee K, Pu Z, Russek SE, Stupic KF, Winter L, Zilberti L, Steckner M. Metrology for MRI: the field you've never heard of. MAGMA (NEW YORK, N.Y.) 2025:10.1007/s10334-025-01238-2. [PMID: 40106079 DOI: 10.1007/s10334-025-01238-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 01/31/2025] [Accepted: 02/14/2025] [Indexed: 03/22/2025]
Abstract
Quantitative MRI has been an active area of research for decades and has produced a huge range of approaches with enormous potential for patient benefit. In many cases, however, there are challenges with reproducibility which have hampered clinical translation. Quantitative MRI is a form of measurement and like any other form of measurement it requires a supporting metrological framework to be fully consistent and compatible with the international system of units. This means not just expressing results in terms of seconds, meters, etc., but demonstrating consistency to their internationally recognized definitions. Such a framework for MRI is not yet complete, but a considerable amount of work has been done internationally towards building one. This article describes the current state of the art for MRI metrology, including a detailed description of metrological principles and how they are relevant to fully quantitative MRI. It also undertakes a gap analysis of where we are versus where we need to be to support reproducibility in MRI. It focusses particularly on the role and activities of national measurement institutes across the globe, illustrating the genuinely international and collaborative nature of the field.
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Affiliation(s)
- Matt G Hall
- National Physical Laboratory, Teddington, UK.
| | | | - Hyo-Min Cho
- Korea Research Institute of Standards and Science, Daejeon, Republic of Korea
| | | | - Kathryn E Keenan
- National Institute of Standards and Technology, Boulder, CO, USA
| | | | - Changwoo Lee
- Korea Research Institute of Standards and Science, Daejeon, Republic of Korea
| | - Chengwei Li
- National Institute of Measurement, Beijing, People's Republic of China
| | | | - Katie Obee
- National Physical Laboratory, Teddington, UK
| | - Zhang Pu
- National Institute of Measurement, Beijing, People's Republic of China
| | - Stephen E Russek
- National Institute of Standards and Technology, Boulder, CO, USA
| | - Karl F Stupic
- National Institute of Standards and Technology, Boulder, CO, USA
| | - Lukas Winter
- Physikalisch-Technische Bundesanstalt, Berlin, Germany
| | - Luca Zilberti
- Istituto Nazionale Di Ricerca Metrologica, Turin, Italy
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Chen H, Cao T, Lin C, Jiao S, He Y, Zhu Z, Guo Q, Wu R, Cai H, Zhang B. Akkermansia muciniphila ameliorates olanzapine-induced metabolic dysfunction-associated steatotic liver disease via PGRMC1/SIRT1/FOXO1 signaling pathway. Front Pharmacol 2025; 16:1550015. [PMID: 40176900 PMCID: PMC11961884 DOI: 10.3389/fphar.2025.1550015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Accepted: 02/26/2025] [Indexed: 04/05/2025] Open
Abstract
Akkermansia muciniphila (AKK), classified as "lean bacteria," has emerged as a promising candidate for ameliorating metabolic disorders, including obesity, diabetes, and liver disease. In this study, we investigated the therapeutic potential of AKK to counteract metabolic dysfunctions induced by Olanzapine (OLZ), a first-class antipsychotic known for its high therapeutic efficacy but also its association with metabolic disturbances, particularly Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Previous studies have implicated progesterone receptor membrane component 1 (PGRMC1) as a key player in antipsychotic-induced metabolic side effects. Using male C57BL/6J mice fed a high-fat diet, we assessed the effects of AKK supplementation on OLZ-induced metabolic disturbances. Key parameters such as body weight, hepatic injury markers, glucose tolerance, insulin resistance, and lipid metabolism were analyzed. The study revealed that AKK supplementation reduced hepatic lipid accumulation, oxidative stress, and insulin resistance, while normalizing lipid and glucose metabolism. These effects are likely mediated through the restoration of PGRMC1/SIRT1/FOXO1 signaling pathway by AKK. Additionally, changes in gut microbiota composition, including a reduction in pathogenic bacteria such as Lactococcus and enrichment of beneficial bacteria, were observed. Overall, the study suggests that AKK has therapeutic potential to counteract OLZ-induced MASLD by modulating gut microbiota and key metabolic pathways, making it a promising strategy for managing metabolic side effects in patients receiving antipsychotic treatment.
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Affiliation(s)
- Hui Chen
- Department of Pharmacy, Changsha Stomatological Hospital, Changsha, Hunan, China
- Department of pharmacy, Institute of Clinical Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China
| | - Ting Cao
- Department of pharmacy, Institute of Clinical Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China
| | - ChenQuan Lin
- Department of pharmacy, Institute of Clinical Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China
| | - ShiMeng Jiao
- Department of pharmacy, Institute of Clinical Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China
| | - YiFang He
- Department of pharmacy, Institute of Clinical Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China
| | - ZhenYu Zhu
- Department of pharmacy, Institute of Clinical Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China
| | - QiuJin Guo
- Department of pharmacy, Institute of Clinical Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China
| | - RenRong Wu
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - HuaLin Cai
- Department of pharmacy, Institute of Clinical Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China
| | - BiKui Zhang
- Department of pharmacy, Institute of Clinical Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China
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Merheb C, Gerbal-Chaloin S, Casas F, Diab-Assaf M, Daujat-Chavanieu M, Feillet-Coudray C. Omega-3 Fatty Acids, Furan Fatty Acids, and Hydroxy Fatty Acid Esters: Dietary Bioactive Lipids with Potential Benefits for MAFLD and Liver Health. Nutrients 2025; 17:1031. [PMID: 40292496 PMCID: PMC11945187 DOI: 10.3390/nu17061031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 03/08/2025] [Accepted: 03/10/2025] [Indexed: 04/30/2025] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common form of chronic liver disease, for which only resmetirom has recently received FDA approval. Prevention is crucial, as it can help manage and potentially reverse the progression of MAFLD to more severe stages. Omega-3 fatty acids, which are a type of polyunsaturated fatty acid (PUFA), have numerous beneficial effects in health and disease, including liver disease. Other bioactive lipids, such as furanic fatty acids (FuFA) and hydroxy fatty acid esters (FAHFA), have also demonstrated several benefits on relevant markers of liver dysfunction in animal and cell models. However, the effects of FAHFAs on hepatic steatosis are inconsistent, and studies on the impact of FuFAs in MAFLD are scarce. Further and more extensive research is required to better understand their role in liver health. The aim of this narrative review is to provide a brief overview of the potential effects of omega-3 fatty acids and other bioactive lipids, such as FuFAs and FAHFAs, on liver disease, with a focus on MAFLD.
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Affiliation(s)
- Camil Merheb
- Institute for Regenerative Medicine and Biotherapy (IRMB), University Montpellier, Institut National de la Santé et de la Recherche Médicale (INSERM), F-34000 Montpellier, France; (C.M.); (S.G.-C.)
| | - Sabine Gerbal-Chaloin
- Institute for Regenerative Medicine and Biotherapy (IRMB), University Montpellier, Institut National de la Santé et de la Recherche Médicale (INSERM), F-34000 Montpellier, France; (C.M.); (S.G.-C.)
| | - François Casas
- Dynamique du Muscle et Métabolisme (DMEM), University Montpellier, Institut National de Recherche pour L’agriculture, L’alimentation et L’environnement (INRAE), F-34295 Montpellier, France; (F.C.); (C.F.-C.)
| | - Mona Diab-Assaf
- Tumorigenesis Molecular and Anticancer Pharmacology, Faculty of Sciences-II, Lebanese University, Beyrouth 1500, Lebanon;
| | - Martine Daujat-Chavanieu
- Institute for Regenerative Medicine and Biotherapy (IRMB), University Montpellier, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Montpellier, F-34000 Montpellier, France
| | - Christine Feillet-Coudray
- Dynamique du Muscle et Métabolisme (DMEM), University Montpellier, Institut National de Recherche pour L’agriculture, L’alimentation et L’environnement (INRAE), F-34295 Montpellier, France; (F.C.); (C.F.-C.)
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40
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Jiang S, Zhang F, Yang H, Han X, Mao J, Zheng G, Fan Y. Estimated sdLDL-C as a biomarker of hepatic steatosis severity in MASLD: a retrospective study. BMC Gastroenterol 2025; 25:168. [PMID: 40082781 PMCID: PMC11907928 DOI: 10.1186/s12876-025-03759-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 03/04/2025] [Indexed: 03/16/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide. However, there is a lack of cost-effective and accurate biomarkers to assess the degree of hepatic steatosis. Estimated small dense low-density lipoprotein cholesterol (EsdLDL-C), a calculated value derived from triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) levels, has emerged as a potential indicator. This study aimed to explore the relationship between EsdLDL-C and the severity of hepatic steatosis. METHODS This single-center retrospective study estimated and directly measured small dense low-density lipoprotein cholesterol (sdLDL-C) in 1,969 patients who underwent serum lipid testing at Changzhou Third People's Hospital between January and July 2024. Among these, 461 patients diagnosed with MASLD were included in the study. These patients were further classified into mild (Mil) and moderate-to-severe (Mod-Sev) groups based on controlled attenuation parameter (CAP) values to explore the relationship between EsdLDL-C and the severity of hepatic steatosis. RESULTS The correlation coefficient (R) between EsdLDL-C and DsdLDL-C was 0.837, with a bias of 0.223. Both EsdLDL-C (OR 1.095, 95% CI 1.029-1.180) and visceral fat area (VFA) (OR 1.019, 95% CI 1.010-1.028) were identified as independent risk factors for Mod-Sev steatosis compared to the Mil group. After adjusting for all confounders, patients with MASLD had a 1.155-fold increased risk of developing Mod-Sev hepatic steatosis for each unit increase in EsdLDL-C. Furthermore, EsdLDL-C demonstrated good predictive value for Mod-Sev steatosis in MASLD patients, with an area under the curve (AUC) of 0.825 (95% CI 0.784-0.867). CONCLUSIONS EsdLDL-C may serve as a practical and cost-effective biomarker for identifying high-risk MASLD patients. TRIAL REGISTRATION The retrospective study was approved by the Ethics Committee of Changzhou Third People's Hospital (02 A-A20230015), and a waiver of informed consent was agreed to, as the data were obtained from medical records, and a waiver of informed consent would not have affected the participants.
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Affiliation(s)
- Shuo Jiang
- Center of Medical Laboratory, Changzhou Third People's Hospital, Changzhou, Jiangsu, China
| | - Fan Zhang
- Department of Endocrinology, Changzhou Third People's Hospital, Changzhou, Jiangsu, China
| | - Hui Yang
- Center of Medical Laboratory, Changzhou Third People's Hospital, Changzhou, Jiangsu, China
| | - Xue Han
- Center of Medical Laboratory, Changzhou Third People's Hospital, Changzhou, Jiangsu, China
| | - Jieru Mao
- Center of Medical Laboratory, Changzhou Third People's Hospital, Changzhou, Jiangsu, China
| | - Guojun Zheng
- Center of Medical Laboratory, Changzhou Third People's Hospital, Changzhou, Jiangsu, China.
| | - Yan Fan
- Center of Medical Laboratory, Changzhou Third People's Hospital, Changzhou, Jiangsu, China.
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Burra P, Cammà C, Invernizzi P, Marra F, Pompili M. Does the hepatologist still need to rely on aminotransferases in clinical practice? A reappraisal of the role of a classic biomarker in the diagnosis and clinical management of chronic liver diseases. Ann Hepatol 2025; 30:101900. [PMID: 40089150 DOI: 10.1016/j.aohep.2025.101900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Accepted: 02/08/2025] [Indexed: 03/17/2025]
Abstract
Aminotransferases, particularly alanine aminotransferase (ALT), are commonly used in the detection, diagnosis, and management of chronic liver diseases. ALT, a sensitive and cost-effective marker of liver injury, remains pivotal in predicting clinical outcomes and guiding interventions in several chronic liver diseases including metabolic dysfunction-associated steatotic liver disease, and chronic viral hepatitis. This study aims to explore the evolving role of ALT as a biomarker. A comprehensive review of evidence was conducted, focusing on studies evaluating ALT thresholds, diagnostic accuracy, and integration with non-invasive liver assessment tools. Special emphasis was given to novel approaches, including artificial intelligence-driven algorithms. Expert opinions from hepatology care perspectives were considered to assess the practical implications of refining ALT-based diagnostic strategies. ALT levels are influenced by diverse factors such as age, gender, and metabolic risks, challenging the use of specific thresholds as biomarker of disease and prognosis. Emerging evidence suggests redefining ALT ranges to enhance sensitivity and accuracy in detecting liver abnormalities. The integration of ALT with advanced non-invasive diagnostic tools, artificial intelligence, and comprehensive patient assessments can optimize early detection of liver disease, thus reducing underdiagnosis, particularly in asymptomatic or vulnerable populations. This work highlights the urgency to tailor the diagnostic approaches in primary and specialised care, ensuring timely and targeted intervention to effectively address the global burden of liver diseases.
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Affiliation(s)
- Patrizia Burra
- Gastroenterology, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Calogero Cammà
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS Fondazione San Gerardo dei Tintori, Monza, Italy; Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Maurizio Pompili
- Department of Medical and Surgical Sciences, Catholic University of the Sacred Heart, A. Gemelli Hospital IRCCS, Rome, Italy
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Nakazawa S, Fukai K, Sano K, Furuya Y, Hoshi K, Kojimahara N, Toyota A, Korenaga M, Tatemichi M. Association of occupational physical activity and sedentary behaviour with the risk of hepatocellular carcinoma: a case-control study based on the Inpatient Clinico-Occupational Database of Rosai Hospital Group. BMJ Open 2025; 15:e092020. [PMID: 40074261 PMCID: PMC11904348 DOI: 10.1136/bmjopen-2024-092020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 02/25/2025] [Indexed: 03/14/2025] Open
Abstract
OBJECTIVES While there is growing evidence that physical activity reduces the risk of hepatocellular carcinoma (HCC), the impact of occupational physical activity and sedentary behaviour remains unclear. This study aimed to investigate the associations between occupational physical activity and sedentary behaviour and HCC risk. DESIGN Matched case-control study. SETTING Nationwide multicentre, hospital-inpatient data set in Japan, from 2005 to 2021. PARTICIPANTS The study included 5625 inpatients diagnosed with HCC and 27 792 matched controls without liver disease or neoplasms. Participants were matched based on sex, age, admission date, and hospital. PRIMARY MEASURES The association between levels of occupational physical activity (low, medium, high) and sedentary time (short, medium, long) with the risk of HCC. SECONDARY MEASURES Stratification of HCC risk by viral infection status (hepatitis B/C virus), alcohol consumption levels and the presence of metabolic diseases (hypertension, diabetes, dyslipidaemia, obesity). RESULTS High occupational physical activity was not associated with HCC caused by hepatitis B/C virus infection in men. In women, high occupational physical activity was associated with a reduced risk of non-viral HCC, with ORs (95% CIs) of 0.65 (0.45-0.93). Among patients with non-viral HCC, medium occupational physical activity combined with medium alcohol intake further decreased the HCC risk in men with an OR of 0.70 (0.50-0.97), while high occupational physical activity combined with lowest alcohol intake decreased the HCC risk in women with an OR of 0.69 (0.48-0.99). Men and women with medium sedentary time had a lower HCC risk compared with those with long sedentary time, with ORs of 0.88 (0.79-0.98) in men and 0.77 (0.62-0.97) in women, respectively. In patients without viral infection or alcohol use, medium sedentary time reduced the HCC risk associated with fatty liver disease without comorbid metabolic diseases in women. CONCLUSIONS High levels of occupational physical activity and/or medium periods of sedentary time are associated with a reduced risk of HCC, particularly non-alcoholic steatohepatitis.
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Affiliation(s)
- Shoko Nakazawa
- Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Kota Fukai
- Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Kei Sano
- Department of Ophthalmology, The Jikei University School of Medicine, Tokyo, Japan
| | - Yuko Furuya
- Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Keika Hoshi
- Center for Health Informatics Policy, National Institute of Public Health, Wako, Japan
- Department of Hygiene, Kitasato University School of Medicine, Sagamihara, Japan
| | - Noriko Kojimahara
- Department of Public Health, Shizuoka Graduate University of Public Health, Shizuoka, Japan
| | - Akihiro Toyota
- Chugoku Rosai Hospital Research Center for the Promotion of Health and Employment Support, Japan Organization of Occupational Health and Safety, Hiroshima, Japan
| | - Masaaki Korenaga
- Hepatitis Information Centre, Research Centre for Hepatitis and Immunology, National Centre for Global Health and Medicine, Ichikawa, Japan
| | - Masayuki Tatemichi
- Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
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Guo W, Weng T, Song Y. Impact of blood lead and manganese levels on metabolic dysfunction-associated steatotic liver disease prevalence: insights from NHANES (2017-2020). BMC Gastroenterol 2025; 25:160. [PMID: 40069625 PMCID: PMC11899840 DOI: 10.1186/s12876-025-03731-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 02/25/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND The metabolic dysfunction-associated steatotic liver disease (MASLD) paradigm represents a significant departure from the previous nonalcoholic fatty liver disease (NAFLD) framework, offering a non-stigmatizing approach that enhances awareness and accelerates patient understanding. Our primary aim was to investigate the potential relationship between blood lead and manganese exposure and the onset of MASLD. METHODS Using data from the National Health and Nutrition Examination Survey (NHANES) database spanning from 2017 to 2020, a cross-sectional study included 4,475 participants was performed to assess the relationship. The statistical analysis used throughout the study included multivariable linear regression and multiple logistic regression models, adjusted for potential confounders to ensure robust and reliable results. We applied a thorough multivariable analysis, examining various factors including age, sex, and ethnicity to enhance the robustness of our findings. RESULTS Employing linear regression models in our study, we observed a clear positive correlation between elevated levels of blood lead and manganese and Controlled attenuation parameter (CAP). Additionally, employing multiple logistic regression models for detailed analysis, we noted a significant increase in the likelihood of MASLD with higher levels of blood lead and manganese. CONCLUSION The findings of this study strongly suggest a notable correlation between increased levels of blood lead and manganese with both CAP and the presence of MASLD. This study represents a population-based approach, enhancing the generalizability of the findings to the broader U.S. POPULATION
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Affiliation(s)
- Wenying Guo
- Ningbo medical center Lihuili Hospital of Ningbo University, Ningbo, 315040, Zhejiang, People's Republic of China
| | - Ting Weng
- Ningbo medical center Lihuili Hospital of Ningbo University, Ningbo, 315040, Zhejiang, People's Republic of China
| | - Yufei Song
- Ningbo medical center Lihuili Hospital of Ningbo University, Ningbo, 315040, Zhejiang, People's Republic of China.
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Kozłowska A. Clinical Insights into Non-Alcoholic Fatty Liver Disease and the Therapeutic Potential of Flavonoids: An Update. Nutrients 2025; 17:956. [PMID: 40289935 PMCID: PMC11944923 DOI: 10.3390/nu17060956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 03/04/2025] [Accepted: 03/06/2025] [Indexed: 04/30/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is considered a significant global health issue related to serious metabolic disorders. However, effective pharmacological treatments are still limited. Flavonoids, a wide group of polyphenol substances, exert anti-inflammatory and lipid-lowering effects in preclinical data. Thus, implementing these research findings in clinical practice could significantly help manage NAFLD and its consequences. This narrative review assesses the therapeutic potential of flavonoids in managing NAFLD. The research collected randomized controlled trials (RCTs) and meta-analyses of RCTs from the past five years concerning the impact of flavonoids on NAFLD. A total of 20 studies were selected according to predetermined inclusion criteria, comprising thirteen randomized controlled trials (RCTs) and seven meta-analyses. The research underscores the beneficial effects of flavonoids in the management of NAFLD through the enhancement of lipid metabolism, the reduction in hepatic steatosis, and the provision of anti-inflammatory actions. Clinical trials demonstrate that interventions rich in flavonoids, including quercetin, epigallocatechin gallate, naringenin, and isoflavones, substantially reduce liver fat content and enhance liver enzyme profiles, with certain compounds exhibiting superior efficacy in particular subgroups, such as older adults and females. Nonetheless, whereas these therapies significantly diminish hepatic steatosis, their effect on fibrosis is constrained. To sum up, flavonoids exhibit significant potential as supplementary treatments for NAFLD by enhancing liver function, lipid metabolism, and inflammation. Additional extensive controlled clinical trials are necessary to create uniform treatment methods and ascertain their long-term therapeutic advantages.
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Affiliation(s)
- Aleksandra Kozłowska
- Department of Social Medicine and Public Health, Medical University of Warsaw, 02-106 Warsaw, Poland
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Berdowska I, Matusiewicz M, Fecka I. A Comprehensive Review of Metabolic Dysfunction-Associated Steatotic Liver Disease: Its Mechanistic Development Focusing on Methylglyoxal and Counterbalancing Treatment Strategies. Int J Mol Sci 2025; 26:2394. [PMID: 40141037 PMCID: PMC11942149 DOI: 10.3390/ijms26062394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 02/21/2025] [Accepted: 03/04/2025] [Indexed: 03/28/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial disorder characterized by excessive lipid accumulation in the liver which dysregulates the organ's function. The key contributor to MASLD development is insulin resistance (IR) which affects many organs (including adipose tissue, skeletal muscles, and the liver), whereas the molecular background is associated with oxidative, nitrosative, and carbonyl stress. Among molecules responsible for carbonyl stress effects, methylglyoxal (MGO) seems to play a major pathological function. MGO-a by-product of glycolysis, fructolysis, and lipolysis (from glycerol and fatty acids-derived ketone bodies)-is implicated in hyperglycemia, hyperlipidemia, obesity, type 2 diabetes, hypertension, and cardiovascular diseases. Its causative effect in the stimulation of prooxidative and proinflammatory pathways has been well documented. Since metabolic dysregulation leading to these pathologies promotes MASLD, the role of MGO in MASLD is addressed in this review. Potential MGO participation in the mechanism of MASLD development is discussed in regard to its role in different signaling routes leading to pathological events accelerating the disorder. Moreover, treatment strategies including approved and potential therapies in MASLD are overviewed and discussed in this review. Among them, medications aimed at attenuating MGO-induced pathological processes are addressed.
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Affiliation(s)
- Izabela Berdowska
- Department of Medical Biochemistry, Faculty of Medicine, Wroclaw Medical University, Chałubińskiego 10, 50-368 Wrocław, Poland;
| | - Małgorzata Matusiewicz
- Department of Medical Biochemistry, Faculty of Medicine, Wroclaw Medical University, Chałubińskiego 10, 50-368 Wrocław, Poland;
| | - Izabela Fecka
- Department of Pharmacognosy and Herbal Medicines, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wrocław, Poland
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Barr B, Levitt DE, Gollahon L. Red Meat Amino Acids for Beginners: A Narrative Review. Nutrients 2025; 17:939. [PMID: 40289994 PMCID: PMC11946737 DOI: 10.3390/nu17060939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 03/04/2025] [Accepted: 03/06/2025] [Indexed: 04/30/2025] Open
Abstract
Meat is a major source of dietary protein and fat across the globe. Red and white meat are the major terms consumers use to refer to types of meat; however, these terms do not fully encompass the range of nutrients provided by meat sources. Red meat refers to meat from mammalian skeletal muscle, while white meat refers to poultry. Red and white meat both provide a wide range of nutritional components in the context of fatty acids, amino acids and micronutrients. Importantly, it has been demonstrated that amino acid profiles differ between red meat and white meat as well as between different sources of red meat. Red meat is a complete source of dietary amino acids, meaning it contains all essential amino acids (EAAs), and in addition, it contains all the non-essential amino acids (NEAAs). Red meat is also the most abundant source of bioavailable heme-iron essential for muscle growth and cardiovascular health. Red meat has been indicated as a major contributor to the rising incidence of metabolic disorders and even colorectal cancer. However, it is important to note that while red meat consumption is linked to these conditions, it is typically the overconsumption of red meat that is associated with obesity and other metabolic symptoms. Similarly, the preparation of red meat is a key factor in its link to colorectal cancer as some methods of preparation produce carcinogens while others do not. Finally, red meat may also be situationally more beneficial to some groups than others, particularly in the cases of sex and aging. For pregnant women, increases in red meat consumption may be beneficial to increase the intake of semi-essential amino acids, while in the elderly, increases in red meat consumption may better preserve muscle mass compared with other dietary protein sources.
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Affiliation(s)
- Benjamin Barr
- Department of Biological Sciences, Texas Tech University, 2500 Main Street, Lubbock, TX 79409, USA;
| | - Danielle E. Levitt
- Department of Kinesiology and Sports Management, Texas Tech University, 3204 Main Street, Lubbock, TX 79409, USA;
| | - Lauren Gollahon
- Department of Biological Sciences, Texas Tech University, 2500 Main Street, Lubbock, TX 79409, USA;
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Nguyen MT, Lian A, Guilford FT, Venketaraman V. A Literature Review of Glutathione Therapy in Ameliorating Hepatic Dysfunction in Non-Alcoholic Fatty Liver Disease. Biomedicines 2025; 13:644. [PMID: 40149620 PMCID: PMC11940638 DOI: 10.3390/biomedicines13030644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 03/01/2025] [Accepted: 03/04/2025] [Indexed: 03/29/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a global cause of liver dysfunction. This spectrum of hepatic disorders can progress to severe conditions, such as non-alcoholic steatohepatitis (NASH) and cirrhosis, due to oxidative stress and sustained cellular injury. With limited pharmacological options, glutathione (GSH), a key antioxidant, has shown promising potential in reducing oxidative stress, maintaining redox balance, and improving liver function. This literature review examines studies from 2014-2024 exploring GSH therapy in NAFLD patients. Eligible studies assessed GSH as the primary intervention for NAFLD in human subjects, reporting outcomes such as liver function or oxidative stress markers. Randomized clinical trials (RCTs) were eligible, while combination therapy studies were included if GSH's effect could be isolated. Exclusions applied to non-NAFLD studies, animal/in vitro models, and non-GSH antioxidant interventions. Analysis of three studies (totaling 109 participants) demonstrated consistent improvements in alanine transaminase (ALT) levels and reductions in oxidative stress markers like 8-hydroxy-2-deoxyguanosine (8-OHdG). However, small sample sizes and inconsistent protocols limit generalizability. Further large-scale RCTs are required to confirm GSH's efficacy, determine optimal dosing, and assess long-term effects. This literature review highlights GSH's potential as a novel NAFLD therapeutic strategy while emphasizing the need for further studies to refine its clinical application.
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Affiliation(s)
- Michelle Thuy Nguyen
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA; (M.T.N.); (A.L.)
| | - Andrew Lian
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA; (M.T.N.); (A.L.)
| | | | - Vishwanath Venketaraman
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA; (M.T.N.); (A.L.)
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Huang DQ, Wong VWS, Rinella ME, Boursier J, Lazarus JV, Yki-Järvinen H, Loomba R. Metabolic dysfunction-associated steatotic liver disease in adults. Nat Rev Dis Primers 2025; 11:14. [PMID: 40050362 DOI: 10.1038/s41572-025-00599-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/07/2025] [Indexed: 03/09/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the umbrella term that comprises metabolic dysfunction-associated steatotic liver, or isolated hepatic steatosis, through to metabolic dysfunction-associated steatohepatitis, the progressive necroinflammatory disease form that can progress to fibrosis, cirrhosis and hepatocellular carcinoma. MASLD is estimated to affect more than one-third of adults worldwide. MASLD is closely associated with insulin resistance, obesity, gut microbial dysbiosis and genetic risk factors. The obesity epidemic and the growing prevalence of type 2 diabetes mellitus greatly contribute to the increasing burden of MASLD. The treatment and prevention of major metabolic comorbidities such as type 2 diabetes mellitus and obesity will probably slow the growth of MASLD. In 2023, the field decided on a new nomenclature and agreed on a set of research and action priorities, and in 2024, the US FDA approved the first drug, resmetirom, for the treatment of non-cirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis. Reliable, validated biomarkers that can replace histology for patient selection and primary end points in MASH trials will greatly accelerate the drug development process. Additionally, noninvasive tests that can reliably determine treatment response or predict response to therapy are warranted. Sustained efforts are required to combat the burden of MASLD by tackling metabolic risk factors, improving risk stratification and linkage to care, and increasing access to therapeutic agents and non-pharmaceutical interventions.
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Affiliation(s)
- Daniel Q Huang
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
| | - Vincent W S Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Mary E Rinella
- University of Chicago Pritzker School of Medicine, Chicago, IL, USA
| | - Jerome Boursier
- Service d'Hépato-Gastroentérologie et Oncologie Digestive, Centre Hospitalier Universitaire d'Angers, Angers, France
- Laboratoire HIFIH, SFR ICAT 4208, Université d'Angers, Angers, France
| | - Jeffrey V Lazarus
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic, University of Barcelona, Barcelona, Spain
- Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
- City University of New York Graduate School of Public Health and Health Policy, New York, NY, USA
| | - Hannele Yki-Järvinen
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Rohit Loomba
- MASLD Research Center, Division of Gastroenterology and Hepatology, University of California at San Diego, San Diego, CA, USA.
- Division of Epidemiology, Department of Family Medicine and Public Health, University of California at San Diego, San Diego, CA, USA.
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Bazargan-Hejazi S, Hines C, Usmani M, Argueta C, Pan D, Brown AF. Racial Disparities in Mortality Rates among Patients with Hepatic Steatosis, Non-Alcoholic Fatty Liver Disease, and Non-Alcoholic Steatohepatitis: Insights from NHANES III Data. J Racial Ethn Health Disparities 2025:10.1007/s40615-025-02317-9. [PMID: 40035953 DOI: 10.1007/s40615-025-02317-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 01/03/2025] [Accepted: 02/14/2025] [Indexed: 03/06/2025]
Abstract
BACKGROUND Insufficient research has been done on NASH-related cirrhosis mortality and potential racial disparities in mortality rates. OBJECTIVE This study aims to analyze racial differences in mortality rates among patients with non-alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver (NAFL), and non-alcoholic steatohepatitis (NASH), hypothesizing that hazard ratios for mortality among patients with NAFLD, NAFL, and NASH would be significantly different for Mexican American patients compared to other racial groups. METHODS Data from NHANES III (1988-1994) representing the U.S. population were analyzed. Bivariate analysis and Cox proportional hazards models were employed to determine mortality rates and predictors across different racial/ethnic groups, adjusting for variables age, gender, smoking status (current, former, non-smoker), BMI (normal, overweight, obese), and a series of biomarkers. RESULTS The prevalence of liver diseases in the sample was: NAFLD (12.1%), NAFL (20.0%), and NASH (3.1%). Deceased patients with NASH had the highest weighted mortality rate (50.6%), followed by NAFLD (39.1%) and NAFL (35.5%). Compared to White patients, Black and Mexican American patients exhibited lower mortality rates for NAFLD. Mexican American patients also had lower mortality rates for NFAL and NASH. White patients showed higher hazard ratios (HR) for NAFLD and NAFL compared to Black and Mexican-American patients. However, for NASH, there were no significant differences in HR between racial/ethnic groups. CONCLUSIONS Despite higher prevalence rates among Mexican American and Black patients, their mortality rates for NAFLD, NAFL, and NASH were comparable or lower than those for Whites. This highlights the need for further research to inform better management and treatment strategies.
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Affiliation(s)
- Shahrzad Bazargan-Hejazi
- Department of Psychiatry and Biobehavioral Sciences, College of Medicine, Charles R. Drew University of Medicine and Science and UCLA David Geffen School of Medicine, Los Angeles, CA, USA.
- Department of Medical Education, Alice L. Walton School of Medicine, Bentonville, USA.
| | - Cameron Hines
- Department of Psychiatry and Biobehavioral Sciences, College of Medicine, Charles R. Drew University of Medicine and Science and UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Myra Usmani
- University of California, Riverside, College of Natural and Agricultural Sciences, Riverside, CA, 92507, USA
| | - Chris Argueta
- College of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA
| | - Deyu Pan
- Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA
| | - Arleen F Brown
- UCLA Ronald Reagan Medical Center and Olive View Medical, Los Angeles, CA, USA
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Dell T, Mesropyan N, Layer Y, Tischler V, Weinhold L, Chang J, Jansen C, Schmidt B, Jürgens M, Isaak A, Kupczyk P, Pieper CC, Meyer C, Luetkens J, Kuetting D. Photon-counting CT-derived Quantification of Hepatic Fat Fraction: A Clinical Validation Study. Radiology 2025; 314:e241677. [PMID: 40100026 DOI: 10.1148/radiol.241677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2025]
Abstract
Background Steatosis is a critical health problem, creating a growing need for opportunistic screening. Early detection may allow for effective treatment and prevention of further liver complications. Purpose To evaluate photon-counting CT (PCCT) fat quantification on contrast-enhanced scans and validate the results against fat quantification via histopathologic assessment, controlled attenuation parameter (CAP) from transient elastography, and MRI proton density fat fraction (PDFF). Materials and Methods In this prospective, observational clinical study, PCCT-derived fat fraction quantification was assessed in participants with known or suspected liver disease. Participants underwent PCCT between February 2022 and January 2024. Participants also underwent biopsy, US with CAP measurement, or MRI with a PDFF sequence for hepatic fat fraction quantification. Liver fat fraction was measured on virtual noncontrast PCCT images using spectral processing software with a three-material decomposition algorithm for fat, liver tissue, and iodine. Steatosis was graded for each modality. Correlation between PCCT-based steatosis grades and biopsy- and CAP-based grades was assessed with the Spearman correlation coefficient. Agreement between PCCT and MRI PDFF measurements was assessed with the intraclass correlation coefficient. Receiver operating characteristic curve analysis was conducted to determine the optimal PCCT fat fraction threshold for distinguishing between participants with and those without steatosis. Results The study included 178 participants, of whom 27 (mean age, 60.7 years ± 15.2 [SD]; 18 male participants) underwent liver biopsy, 26 (mean age, 60.0 years ± 18.3; 15 male participants) underwent CAP measurement, and 125 (mean age, 61.2 years ± 13.1; 70 male participants) underwent MRI PDFF measurement. There was excellent agreement between PCCT and MRI PDFF assessment of liver fat fraction (intraclass correlation coefficient, 0.91 [95% CI: 0.87, 0.94]). In stratified analysis, the intraclass correlation coefficient was 0.84 (95% CI: 0.63, 0.93) in participants with known fibrosis and 0.92 (95% CI: 0.88, 0.94) in participants without fibrosis. There was moderate correlation of PCCT-based steatosis grade with histologic (ρ = 0.65) and CAP-based (ρ = 0.45) steatosis grade. Based on the Youden index, the PCCT fat fraction threshold that best discriminated between participants with and those without steatosis was 4.8%, with a maximum achievable sensitivity of 81% (38 of 47) and a specificity of 71% (55 of 78). Conclusion PCCT in a standard clinical setting allowed for accurate estimation of liver fat fraction compared with MRI PDFF-based reference standard measurements. © RSNA, 2025 See also the editorial by Kartalis and Grigoriadis in this issue.
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Affiliation(s)
- Tatjana Dell
- Department of Diagnostic and Interventional Radiology and Quantitative Imaging Lab Bonn, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
| | - Narine Mesropyan
- Department of Diagnostic and Interventional Radiology and Quantitative Imaging Lab Bonn, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
| | - Yannik Layer
- Department of Diagnostic and Interventional Radiology and Quantitative Imaging Lab Bonn, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
| | - Verena Tischler
- Institute of Pathology, University Hospital Bonn, Bonn, Germany
| | - Leonie Weinhold
- Institute for Medical Biometry, Informatics, and Epidemiology, Rhenish Friedrich Wilhelm University of Bonn, Bonn, Germany
| | - Johannes Chang
- Department of Internal Medicine I, Center for Cirrhosis and Portal Hypertension Bonn, University Hospital Bonn, Bonn, Germany
| | - Christian Jansen
- Department of Internal Medicine I, Center for Cirrhosis and Portal Hypertension Bonn, University Hospital Bonn, Bonn, Germany
| | - Bernhard Schmidt
- Department of Computed Tomography, Siemens Healthcare, Forchheim, Germany
| | - Markus Jürgens
- Department of Computed Tomography, Siemens Healthcare, Forchheim, Germany
| | - Alexander Isaak
- Department of Diagnostic and Interventional Radiology and Quantitative Imaging Lab Bonn, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
| | - Patrick Kupczyk
- Department of Diagnostic and Interventional Radiology and Quantitative Imaging Lab Bonn, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
| | - Claus Christian Pieper
- Department of Diagnostic and Interventional Radiology and Quantitative Imaging Lab Bonn, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
| | - Carsten Meyer
- Department of Diagnostic and Interventional Radiology and Quantitative Imaging Lab Bonn, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
| | - Julian Luetkens
- Department of Diagnostic and Interventional Radiology and Quantitative Imaging Lab Bonn, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
| | - Daniel Kuetting
- Department of Diagnostic and Interventional Radiology and Quantitative Imaging Lab Bonn, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
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