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Sharma H, Anand A, Halagali P, Inamdar A, Pathak R, Taghizadeh‐Hesary F, Ashique S. Advancement of Nanoengineered Flavonoids for Chronic Metabolic Diseases. ROLE OF FLAVONOIDS IN CHRONIC METABOLIC DISEASES 2024:459-510. [DOI: 10.1002/9781394238071.ch13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Lonardo A, Weiskirchen R. Copper and liver fibrosis in MASLD: the two-edged sword of copper deficiency and toxicity. METABOLISM AND TARGET ORGAN DAMAGE 2024. [DOI: 10.20517/mtod.2024.47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Copper is a trace metal whose absence or deficiency can cause structural and functional alterations that can be corrected by copper administration. Copper excess is associated with significant liver toxicity, such as that seen in Wilson’s disease, which often exhibits liver steatosis and can be managed by copper sequestrants. Copper, due to its ability to either accept or donate electrons, is a cofactor in many physiological redox reactions, playing an essential role in cell energy homeostasis, detoxification of reactive oxygen species, and hepatic immunometabolism. Given these facts, it is reasonable to speculate that copper might be involved in the pathogenesis of liver fibrosis in the setting of metabolic dysfunction-associated fatty liver disease (MASLD). To address this research question, a narrative review of published studies was conducted, spanning from the needs, sources, and toxicity of copper to Menkes and Wilson’s disease. Most epidemiological studies have demonstrated that MASLD is associated with copper deficiency. However, several studies show that MASLD is associated with copper excess and very few conclude that copper is not associated with MASLD. Therefore, the putative pathomechanisms associating both copper excess and deficiency with MASLD development and progression are reviewed. In conclusion, epidemiological and pathogenic data support the notion that well-balanced copper homeostasis is a prerequisite for liver health. Accordingly, both copper excess and deficiency may potentially predispose to liver fibrosis via the development of MASLD. Therefore, studies aimed at restoring normal bodily stores of copper should be tailored according to precision medicine approaches based on the specific features of copper metabolism in individual MASLD patients.
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Dauwe Y, Mary L, Oliviero F, Dubois L, Rousseau-Bacquie E, Gomez J, Gayrard V, Mselli-Lakhal L. Synergistic Steatosis Induction in Mice: Exploring the Interactions and Underlying Mechanisms between PFOA and Tributyltin. Cells 2024; 13:940. [PMID: 38891072 PMCID: PMC11171786 DOI: 10.3390/cells13110940] [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: 03/29/2024] [Revised: 05/21/2024] [Accepted: 05/28/2024] [Indexed: 06/21/2024] Open
Abstract
This study explores the impact of environmental pollutants on nuclear receptors (CAR, PXR, PPARα, PPARγ, FXR, and LXR) and their heterodimerization partner, the Retinoid X Receptor (RXR). Such interaction may contribute to the onset of non-alcoholic fatty liver disease (NAFLD), which is initially characterized by steatosis and potentially progresses to steatohepatitis and fibrosis. Epidemiological studies have linked NAFLD occurrence to the exposure to environmental contaminants like PFAS. This study aims to assess the simultaneous activation of nuclear receptors via perfluorooctanoic acid (PFOA) and RXR coactivation via Tributyltin (TBT), examining their combined effects on steatogenic mechanisms. Mice were exposed to PFOA (10 mg/kg/day), TBT (5 mg/kg/day) or a combination of them for three days. Mechanisms underlying hepatic steatosis were explored by measuring nuclear receptor target gene and lipid metabolism key gene expressions, by quantifying plasma lipids and hepatic damage markers. This study elucidated the involvement of the Liver X Receptor (LXR) in the combined effect on steatosis and highlighted the permissive nature of the LXR/RXR heterodimer. Antagonistic effects of TBT on the PFOA-induced activation of the Pregnane X Receptor (PXR) and Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) were also observed. Overall, this study revealed complex interactions between PFOA and TBT, shedding light on their combined impact on liver health.
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Affiliation(s)
| | | | | | | | | | | | | | - Laïla Mselli-Lakhal
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, Institut National de Recherche Pour L’agriculture, L’alimentation et L’environnement (INRAE), Ecole Nationale Veterinaire de Toulouse (ENVT), INP-Purpan, Université Paul Sabatier (UPS), 31027 Toulouse, France; (Y.D.); (L.M.); (F.O.); (L.D.); (E.R.-B.); (J.G.); (V.G.)
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Lonardo A. Association of NAFLD/NASH, and MAFLD/MASLD with chronic kidney disease: an updated narrative review. METABOLISM AND TARGET ORGAN DAMAGE 2024; 4. [DOI: 10.20517/mtod.2024.07] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) account for substantial financial burden worldwide. These alarming features call for enhanced efforts to prevent and manage the development and progression of CKD. Accumulating evidence supporting a causal role of NAFLD/MAFLD/MASLD-in CKD opens new horizons to achieve this aim. Recent epidemiological studies and meta-analyses exploring the association of NAFLD/MAFLD/MASLD with CKD and the characteristics of NAFLD/MAFLD/MASLD associated with the odds of incident CKD are discussed. The involved pathomechanisms, including the common soil hypothesis, genetics, gut dysbiosis, and portal hypertension, are examined in detail. Finally, lifestyle changes (diet and physical exercise), direct manipulation of gut microbiota, and drug approaches involving statins, renin-angiotensin-aldosterone system inhibitors, GLP-1 Receptor Agonists, Sodium-glucose cotransporter-2, pemafibrate, and vonafexor are examined within the context of prevention and management of CKD among those with NAFLD/MAFLD/MASLD. The evolving NAFLD/MAFLD/MASLD nomenclature may generate confusion among practicing clinicians and investigators. However, comparative studies investigating the pros and contra of different nomenclatures may identify the most useful definitions among NAFLD/MAFLD/MASLD and strategies to identify, prevent, and halt the onset and progression of CKD.
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Jia L, Yang Y, Sun F, Tao H, Lu C, Yang JJ. Mitochondrial quality control in liver fibrosis: Epigenetic hallmarks and therapeutic strategies. Cell Signal 2024; 115:111035. [PMID: 38182067 DOI: 10.1016/j.cellsig.2024.111035] [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: 12/06/2023] [Revised: 12/29/2023] [Accepted: 01/01/2024] [Indexed: 01/07/2024]
Abstract
BACKGROUND AND AIM Mitochondrial quality control (MQC) plays a significant role in the progression of liver fibrosis, with key processes such as mitochondrial fission, fusion, mitophagy and biogenesis maintaining mitochondrial homeostasis. To understand the molecular mechanisms underlying epigenetic regulation of mitochondrial quality control in liver fibrosis, with the aim of uncovering novel therapeutic targets for treating, mitigating, and potentially reversing liver fibrosis, in light of the most recent advances in this field. METHODS We searched PubMed, Web of Science, and Scopus for published manuscripts using terms "mitochondrial quality control" "mitochondrial fission" "mitochondrial fusion" "mitochondrial biogenesis" "mitophagy" "liver fibrosis" "epigenetic regulation" "DNA methylation" "RNA methylation" "histone modification" and "non-coding RNA". Manuscripts were collated, studied and carried forward for discussion where appropriate. RESULTS Mitochondrial fission, fusion, biogenesis, and mitophagy regulate the homeostasis of mitochondria, and the imbalance of mitochondrial homeostasis can induce liver fibrosis. Epigenetic regulation, including DNA methylation, RNA methylation, histone modifications, and non-coding RNAs, plays a significant role in regulating the processes of mitochondrial homeostasis. CONCLUSION Mitochondrial quality control and epigenetic mechanisms are intricately linked to the pathogenesis of liver fibrosis. Understanding these molecular interactions provides insight into potential therapeutic strategies. Further research is necessary to translate these findings into clinical applications, with a focus on developing epigenetic drugs to ameliorate liver fibrosis by modulating MQC and epigenetic pathways.
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Affiliation(s)
- Lin Jia
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Yang Yang
- Department of General Surgery, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou 215153, China
| | - Feng Sun
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Hui Tao
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China.
| | - Chao Lu
- School of Pharmacy, Anhui Medical University, Hefei 230032, China; First Affiliated Hospital, Anhui University of Science & Technology, Huainan 232001, China.
| | - Jing-Jing Yang
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
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Dauwe Y, Mary L, Oliviero F, Grimaldi M, Balaguer P, Gayrard V, Mselli-Lakhal L. Steatosis and Metabolic Disorders Associated with Synergistic Activation of the CAR/RXR Heterodimer by Pesticides. Cells 2023; 12:cells12081201. [PMID: 37190111 DOI: 10.3390/cells12081201] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 04/18/2023] [Accepted: 04/19/2023] [Indexed: 05/17/2023] Open
Abstract
The nuclear receptor, constitutive androstane receptor (CAR), which forms a heterodimer with the retinoid X receptor (RXR), was initially reported as a transcription factor that regulates hepatic genes involved in detoxication and energy metabolism. Different studies have shown that CAR activation results in metabolic disorders, including non-alcoholic fatty liver disease, by activating lipogenesis in the liver. Our objective was to determine whether synergistic activations of the CAR/RXR heterodimer could occur in vivo as described in vitro by other authors, and to assess the metabolic consequences. For this purpose, six pesticides, ligands of CAR, were selected, and Tri-butyl-tin (TBT) was used as an RXR agonist. In mice, CAR's synergic activation was induced by dieldrin associated with TBT, and combined effects were induced by propiconazole, bifenox, boscalid, and bupirimate. Moreover, a steatosis, characterized by increased triglycerides, was observed when TBT was combined with dieldrin, propiconazole, bifenox, boscalid, and bupirimate. Metabolic disruption appeared in the form of increased cholesterol and lowered free fatty acid plasma levels. An in-depth analysis revealed increased expression of genes involved in lipid synthesis and lipid import. These results contribute to the growing understanding of how environmental contaminants can influence nuclear receptor activity and associated health risks.
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Affiliation(s)
- Yannick Dauwe
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France
| | - Lucile Mary
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France
| | - Fabiana Oliviero
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France
| | - Marina Grimaldi
- Institut de Recherche en Cancérologie de Montpellier, Inserm U1194-Université Montpellier-Institut régional du Cancer Montpellier, CEDEX 5, F-34298 Montpellier, France
| | - Patrick Balaguer
- Institut de Recherche en Cancérologie de Montpellier, Inserm U1194-Université Montpellier-Institut régional du Cancer Montpellier, CEDEX 5, F-34298 Montpellier, France
| | - Véronique Gayrard
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France
| | - Laïla Mselli-Lakhal
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France
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Xu J, Wei Y, Huang Y, Wei X. Regulatory Effects and Molecular Mechanisms of Tea and Its Active Compounds on Nonalcoholic Fatty Liver Disease. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:3103-3124. [PMID: 36773311 DOI: 10.1021/acs.jafc.2c07702] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease, is a multifactorial disease resulting from the interaction between environment, genetic background, and metabolic stress. Most treatments for NAFLD include dietary intervention and exercise show limited efficacy due to the complex mechanisms involved in NAFLD. Meanwhile, drug therapy is accompanied by serious side effects. The development of high-efficiency natural supplements is a sustainable strategy for the prevention and treatment of NAFLD. As the second most consumed beverage, tea has health benefits that have been widely recognized. Nevertheless, the intervention of tea active compounds in NAFLD has received limited attention. Tea contains abundant bioactive compounds with potential effects on NAFLD, such as catechins, flavonoids, theanine, tea pigments, and tea polysaccharides. We reviewed the intrinsic and environmental factors and pathogenic mechanisms that affect the occurrence and development of NAFLD, and summarized the influences of exercise, drugs, diet, and tea drinking on NAFLD. On this basis, we further analyzed the potential effects and molecular regulatory mechanisms of tea active compounds on NAFLD and proposed future development directions. This review hopes to provide novel insights into the development and application of tea active compounds in the prevention and treatment of NAFLD.
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Affiliation(s)
- Jia Xu
- School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
- School of Environmental and Chemical Engineering, Shanghai University, 333 Nanchen Road, Shanghai 200240, PR China
| | - Yang Wei
- School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
| | - Yi Huang
- School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
| | - Xinlin Wei
- School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
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Shiragannavar VD, Sannappa Gowda NG, Puttahanumantharayappa LD, Karunakara SH, Bhat S, Prasad SK, Kumar DP, Santhekadur PK. The ameliorating effect of withaferin A on high-fat diet-induced non-alcoholic fatty liver disease by acting as an LXR/FXR dual receptor activator. Front Pharmacol 2023; 14:1135952. [PMID: 36909161 PMCID: PMC9995434 DOI: 10.3389/fphar.2023.1135952] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 02/07/2023] [Indexed: 02/25/2023] Open
Abstract
Introduction: Non-alcoholic fatty liver disease (NAFLD) incidence has been rapidly increasing, and it has emerged as one of the major diseases of the modern world. NAFLD constitutes a simple fatty liver to chronic non-alcoholic steatohepatitis (NASH), which often leads to liver fibrosis or cirrhosis, a serious health condition with limited treatment options. Many a time, NAFLD progresses to fatal hepatocellular carcinoma (HCC). Nuclear receptors (NRs), such as liver X receptor-α (LXR-α) and closely associated farnesoid X receptor (FXR), are ligand-inducible transcription factors that regulate various metabolism-associated gene expressions and repression and play a major role in controlling the pathophysiology of the human liver. Withaferin A is a multifaceted and potent natural dietary compound with huge beneficial properties and plays a vital role as an anti-inflammatory molecule. Methods: In vivo: Swill albino mice were fed with western diet and sugar water (WDSW) for 12, 16, and 20 weeks with suitable controls. Post necropsy, liver enzymes (AST, ALT, and ALP) and lipid profile were measured by commercially available kits using a semi-auto analyzer in serum samples. Liver histology was assessed using H&E and MTS stains to check the inflammation and fibrosis, respectively, using paraffin-embedded sections and mRNA expressions of these markers were measured using qRT-PCR method. TGF-β1 levels in serum samples were quantified by ELISA. In vitro: Steatosis was induced in HepG2 and Huh7 cells using free fatty acids [Sodium Palmitate (SP) and Oleate (OA)]. After induction, the cells were treated with Withaferin A in dose-dependent manner (1, 2.5, and 5 μM, respectively). In vitro steatosis was confirmed by Oil-Red-O staining. Molecular Docking: Studies were conducted using Auto Dock Vina software to check the binding affinity of Withaferin-A to LXR-α and FXR. Results: We explored the dual receptor-activating nature of Withaferin A using docking studies, which potently improves high-fat diet-induced NAFLD in mice and suppresses diet-induced hepatic inflammation and liver fibrosis via LXR/FXR. Our in vitro studies also indicated that Withaferin A inhibits lipid droplet accumulation in sodium palmitate and oleate-treated HepG2 and Huh7 cells, which may occur through LXR-α and FXR-mediated signaling pathways. Withaferin A is a known inhibitor of NF-κB-mediated inflammation. Intriguingly, both LXR-α and FXR activation inhibits inflammation and fibrosis by negatively regulating NF-κB. Additionally, Withaferin A treatment significantly inhibited TGF-β-induced gene expression, which contributes to reduced hepatic fibrosis. Discussion: Thus, the LXR/ FXR dual receptor activator Withaferin A improves both NAFLD-associated liver inflammation and fibrosis in mouse models and under in vitro conditions, which makes Withaferin A a possibly potent pharmacological and therapeutic agent for the treatment of diet-induced NAFLD.
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Affiliation(s)
- Varsha D Shiragannavar
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Nirmala G Sannappa Gowda
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Lakshana D Puttahanumantharayappa
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Shreyas H Karunakara
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Smitha Bhat
- Department of Biotechnology and Bioinformatics, JSS Academy of Higher Education and Research, Mysore, Karnataka, India
| | - Shashanka K Prasad
- Department of Biotechnology and Bioinformatics, JSS Academy of Higher Education and Research, Mysore, Karnataka, India.,Bioactive Compound Laboratory, Faculty of Agriculture, Chiang Mai University, Chiang Mai, Thailand
| | - Divya P Kumar
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Prasanna K Santhekadur
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
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Ethanol Extract of Pinus koraiensis Leaves Mitigates High Fructose-Induced Hepatic Triglyceride Accumulation and Hypertriglyceridemia. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12136745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Pinus koraiensis is a valuable plant source of functional health foods and medicinal materials. Hypertriglyceridemia affects about 15–20% of adults and is related to stroke, metabolic syndromes, cardiovascular diseases, and diabetes mellitus. Dietary fructose, a risk factor for developing hypertriglyceridemia, significantly increases postprandial triglyceride (TG) levels and aggravates non-alcoholic fatty liver disease. In this study, we aimed to analyze the effect of ethanol extract from P. koraiensis needles (EPK) on fructose (Fr)-induced cell culture and animal models, respectively. Our team determined the bioactivity, such as anti-cancer, anti-obesity, anti-diabetic, and anti-hyperlipidemic functions, of P. koraiensis needle extract. The EPK markedly reduced TG levels in the liver and serum and enhanced TG excretion through feces in high-fructose-fed rats. Furthermore, the EPK inhibited de novo lipogenesis and its markers—carbohydrate response element-binding protein (ChREBP), sterol regulatory element-binding protein 1 (SREBP-1), fatty acid synthase (FAS), 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), and tumor necrosis factor-alpha (TNF-α), a pro-inflammatory marker. Consistent with the results of the in vivo experiment, the EPK decreased SREBP-1, ChREBP, HMGCR, FAS, TNF-α, and iNOS expression levels, resulting in slower lipid accumulation and lower TG levels in Fr-induced HepG2 cells. These findings suggest that EPK mitigates hypertriglyceridemia and hepatic TG accumulation by inhibiting de novo lipogenic and pro-inflammatory factors.
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Puengel T, Liu H, Guillot A, Heymann F, Tacke F, Peiseler M. Nuclear Receptors Linking Metabolism, Inflammation, and Fibrosis in Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2022; 23:ijms23052668. [PMID: 35269812 PMCID: PMC8910763 DOI: 10.3390/ijms23052668] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/23/2022] [Accepted: 02/26/2022] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) and its progressive form nonalcoholic steatohepatitis (NASH) comprise a spectrum of chronic liver diseases in the global population that can lead to end-stage liver disease and hepatocellular carcinoma (HCC). NAFLD is closely linked to the metabolic syndrome, and comorbidities such as type 2 diabetes, obesity and insulin resistance aggravate liver disease, while NAFLD promotes cardiovascular risk in affected patients. The pathomechanisms of NAFLD are multifaceted, combining hepatic factors including lipotoxicity, mechanisms of cell death and liver inflammation with extrahepatic factors including metabolic disturbance and dysbiosis. Nuclear receptors (NRs) are a family of ligand-controlled transcription factors that regulate glucose, fat and cholesterol homeostasis and modulate innate immune cell functions, including liver macrophages. In parallel with metabolic derangement in NAFLD, altered NR signaling is frequently observed and might be involved in the pathogenesis. Therapeutically, clinical data indicate that single drug targets thus far have been insufficient for reaching patient-relevant endpoints. Therefore, combinatorial treatment strategies with multiple drug targets or drugs with multiple mechanisms of actions could possibly bring advantages, by providing a more holistic therapeutic approach. In this context, peroxisome proliferator-activated receptors (PPARs) and other NRs are of great interest as they are involved in wide-ranging and multi-organ activities associated with NASH progression or regression. In this review, we summarize recent advances in understanding the pathogenesis of NAFLD, focusing on mechanisms of cell death, immunometabolism and the role of NRs. We outline novel therapeutic strategies and discuss remaining challenges.
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Affiliation(s)
- Tobias Puengel
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, 13353 Berlin, Germany; (T.P.); (H.L.); (A.G.); (F.H.)
- Berlin Institute of Health (BIH), 10178 Berlin, Germany
| | - Hanyang Liu
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, 13353 Berlin, Germany; (T.P.); (H.L.); (A.G.); (F.H.)
| | - Adrien Guillot
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, 13353 Berlin, Germany; (T.P.); (H.L.); (A.G.); (F.H.)
| | - Felix Heymann
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, 13353 Berlin, Germany; (T.P.); (H.L.); (A.G.); (F.H.)
| | - Frank Tacke
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, 13353 Berlin, Germany; (T.P.); (H.L.); (A.G.); (F.H.)
- Correspondence: (F.T.); (M.P.)
| | - Moritz Peiseler
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, 13353 Berlin, Germany; (T.P.); (H.L.); (A.G.); (F.H.)
- Berlin Institute of Health (BIH), 10178 Berlin, Germany
- Correspondence: (F.T.); (M.P.)
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Lee D, Trinh TA, Shin MS, Kang KS. Adipose tissue. RECENT ADVANCEMENTS IN MICROBIAL DIVERSITY 2022:209-228. [DOI: 10.1016/b978-0-12-822368-0.00009-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Robeva R, Mladenović D, Vesković M, Hrnčić D, Bjekić-Macut J, Stanojlović O, Livadas S, Yildiz BO, Macut D. The interplay between metabolic dysregulations and non-alcoholic fatty liver disease in women after menopause. Maturitas 2021; 151:22-30. [PMID: 34446275 DOI: 10.1016/j.maturitas.2021.06.012] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/18/2021] [Accepted: 06/26/2021] [Indexed: 12/12/2022]
Abstract
The hypoestrogenic period after menopause and associated metabolic imbalance might facilitate the onset of non-alcoholic fatty liver disease (NAFLD) and its progression. The prevalence of NAFLD increases in patients experiencing premature ovarian insufficiency, as well as surgical or natural menopause. The postmenopausal period is characterized by dyslipidemia and insulin resistance associated with an increased influx of free fatty acids to the liver with consequent steatosis and further progression of NAFLD. More than half of postmenopausal women with diabetes mellitus type 2 suffer from NAFLD. It is suggested that estrogens slow the progression of chronic liver diseases by suppression of inflammation, improvement of mitochondrial function, alleviation of oxidative stress, insulin resistance, and fibrogenesis. The hyperandrogenic state of polycystic ovary syndrome (PCOS) is associated with the development of NAFLD in women of reproductive age, but it is difficult to extend these findings to menopause due to inappropriate diagnosis of PCOS after menopause. Lifestyle intervention, including physical activity and dietary regimens, remains the first-line preventive and therapeutic option for NAFLD. There are contradictory reports on the use of menopausal hormonal therapy (MHT) and NAFLD. It is necessary to investigate the potential effects of estradiol dose, progesterone type, selective estrogen receptor modulators and tissue-selective estrogen complex compounds on NAFLD development and progression in postmenopausal women. The present review aims to explore the pathophysiological and clinical aspects of liver metabolic disturbances in women after menopause, focusing on the possible preventive and therapeutic strategies in NAFLD, including the potential role of MHT.
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Affiliation(s)
- Ralitsa Robeva
- Department of Endocrinology, USHATE "Acad. Iv. Penchev", Faculty of Medicine, Medical University-Sofia, Sofia, Bulgaria
| | - Dušan Mladenović
- Institute of Pathophysiology "Ljubodrag Buba Mihailović", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Milena Vesković
- Institute of Pathophysiology "Ljubodrag Buba Mihailović", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Dragan Hrnčić
- Institute of Medicinal Physiology "Richard Burian", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Jelica Bjekić-Macut
- Department of Endocrinology, CHC Bežanijska kosa, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Olivera Stanojlović
- Institute of Medicinal Physiology "Richard Burian", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | | | - Bulent O Yildiz
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Hacettepe University School of Medicine, Ankara, Turkey
| | - Djuro Macut
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Faculty of Medicine, University of Belgrade, Dr Subotića 13, 11000 Belgrade, Serbia.
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Abstract
The objective of chronotherapy is to optimize medical treatments taking into account the body's circadian rhythms. Chronotherapy is referred to and practiced in two different ways: (1) to alter the sleep-wake rhythms of patients to improve the sequels of several pathologies; (2) to take into account the circadian rhythms of patients to improve therapeutics. Even minor dysfunction of the biological clock can greatly affect sleep/wake physiology causing excessive diurnal somnolence, increase in sleep onset latency, phase delays or advances in sleep onset, frequent night awakenings, reduced sleep efficiency, delayed and shortened rapid eye movement sleep, or increased periodic leg movements. Chronotherapy aims to restore the proper circadian pattern of the sleep-wake cycle, through adequate sleep hygiene, timed light exposure, and the use of chronobiotic medications, such as melatonin, that affect the output phase of circadian rhythms, thus controlling the clock. Concerning the second use of chronotherapy, therapeutic outcomes as diverse as the survival after open-heart surgery or the efficacy and tolerance to chemotherapy vary according to the time of day. However, humans are heterogeneous concerning the timing of their internal clocks. Not only different chronotypes exist but also the endogenous human circadian period (τ) is not a stable trait as it depends on many internal and external factors. If any scheduled therapeutic intervention is going to be optimized, a tool is needed for simple diagnostic and objectively measurement of an individual's internal time at any given time. Methodologic advances like the use of single-sample gene expression and metabolomics are discussed.
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Affiliation(s)
- Daniel P Cardinali
- Faculty of Medical Sciences, Pontificia Universidad Católica Argentina, Buenos Aires, Argentina
| | - Gregory M Brown
- Department of Psychiatry, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada
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14
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Lamos EM, Kristan M, Siamashvili M, Davis SN. Effects of anti-diabetic treatments in type 2 diabetes and fatty liver disease. Expert Rev Clin Pharmacol 2021; 14:837-852. [PMID: 33882758 DOI: 10.1080/17512433.2021.1917374] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are significant non-communicable diseases that often affect individuals concurrently. In individuals with both T2DM and NAFLD, there is evidence that anti-diabetic therapies may demonstrate potential combined beneficial metabolic and reduced hepatic inflammatory effects.Areas covered: A PubMed and Google Scholar search was performed to find relevant literature. Included studies focused on individuals with T2DM and NAFLD receiving anti-diabetic treatments including bariatric surgery, insulin sensitizers, incretin mimetics, and SGLT2 inhibitors. Additional articles highlight investigational treatments.Expert opinion: In individuals with T2DM and NAFLD, 5-10% weight loss or bariatric surgery if unable to lose weight or maintain weight loss are appropriate. GLP-1 receptor agonists and SGLT2 inhibitors result in weight loss, appear safe and may provide beneficial hepatic outcomes. Whether their effects are related to favorable weight changes or intrinsic hepatic effects is unclear. Thiazolidinediones have advantageous anti-hyperglycemic and hepatic effects but individuals must be monitored for weight gain and edema. Metformin and DPP-4 inhibitor beneficial hepatic effects remain debated. There are opportunities to standardize markers and imaging of NAFLD. Studies powered to evaluate the possible cardiovascular benefits of anti-diabetic therapies in individuals with T2DM and NAFLD are needed.
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Affiliation(s)
- Elizabeth M Lamos
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Megan Kristan
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Maka Siamashvili
- Department of Medicine, University of Maryland Medical Center, Baltimore, MD, USA
| | - Stephen N Davis
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
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15
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Kaneto H, Obata A, Kimura T, Shimoda M, Kinoshita T, Matsuoka TA, Kaku K. Unexpected Pleiotropic Effects of SGLT2 Inhibitors: Pearls and Pitfalls of This Novel Antidiabetic Class. Int J Mol Sci 2021; 22:ijms22063062. [PMID: 33802741 PMCID: PMC8002535 DOI: 10.3390/ijms22063062] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/13/2021] [Accepted: 03/14/2021] [Indexed: 02/06/2023] Open
Abstract
Sodium-glucose co-transporter 2 (SGLT2) inhibitors facilitate urine glucose excretion by reducing glucose reabsorption, leading to ameliorate glycemic control. While the main characteristics of type 2 diabetes mellitus are insufficient insulin secretion and insulin resistance, SGLT2 inhibitors have some favorable effects on pancreatic β-cell function and insulin sensitivity. SGLT2 inhibitors ameliorate fatty liver and reduce visceral fat mass. Furthermore, it has been noted that SGLT2 inhibitors have cardio-protective and renal protective effects in addition to their glucose-lowering effect. In addition, several kinds of SGLT2 inhibitors are used in patients with type 1 diabetes mellitus as an adjuvant therapy to insulin. Taken together, SGLT2 inhibitors have amazing multifaceted effects that are far beyond prediction like some emerging magical medicine. Thereby, SGLT2 inhibitors are very promising as relatively new anti-diabetic drugs and are being paid attention in various aspects. It is noted, however, that SGLT2 inhibitors have several side effects such as urinary tract infection or genital infection. In addition, we should bear in mind the possibility of diabetic ketoacidosis, especially when we use SGLT2 inhibitors in patients with poor insulin secretory capacity.
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Affiliation(s)
- Hideaki Kaneto
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192, Japan; (A.O.); (T.K.); (M.S.); (T.K.)
- Correspondence:
| | - Atsushi Obata
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192, Japan; (A.O.); (T.K.); (M.S.); (T.K.)
| | - Tomohiko Kimura
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192, Japan; (A.O.); (T.K.); (M.S.); (T.K.)
| | - Masashi Shimoda
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192, Japan; (A.O.); (T.K.); (M.S.); (T.K.)
| | - Tomoe Kinoshita
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192, Japan; (A.O.); (T.K.); (M.S.); (T.K.)
| | - Taka-aki Matsuoka
- The First Department of Internal Medicine, Wakayama Medical University, Wakayama 641-8510, Japan;
| | - Kohei Kaku
- Department of General Internal Medicine 1, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192, Japan;
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16
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Libby AE, Jones B, Lopez-Santiago I, Rowland E, Levi M. Nuclear receptors in the kidney during health and disease. Mol Aspects Med 2020; 78:100935. [PMID: 33272705 DOI: 10.1016/j.mam.2020.100935] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 10/24/2020] [Accepted: 11/16/2020] [Indexed: 02/06/2023]
Abstract
Over the last 30 years, nuclear receptors (NRs) have been increasingly recognized as key modulators of systemic homeostasis and as contributing factors in many diseases. In the kidney, NRs play numerous important roles in maintaining homeostasis-many of which continue to be unraveled. As "master regulators", these important transcription factors integrate and coordinate many renal processes such as circadian responses, lipid metabolism, fatty acid oxidation, glucose handling, and inflammatory responses. The use of recently-developed genetic tools and small molecule modulators have allowed for detailed studies of how renal NRs contribute to kidney homeostasis. Importantly, while NRs are intimately involved in proper kidney function, they are also implicated in a variety of renal diseases such as diabetes, acute kidney injury, and other conditions such as aging. In the last 10 years, our understanding of renal disease etiology and progression has been greatly shaped by knowledge regarding how NRs are dysregulated in these conditions. Importantly, NRs have also become attractive therapeutic targets for attenuation of renal diseases, and their modulation for this purpose has been the subject of intense investigation. Here, we review the role in health and disease of six key renal NRs including the peroxisome proliferator-activated receptors (PPAR), estrogen-related receptors (ERR), the farnesoid X receptors (FXR), estrogen receptors (ER), liver X receptors (LXR), and vitamin D receptors (VDR) with an emphasis on recent findings over the last decade. These NRs have generated a wealth of data over the last 10 years that demonstrate their crucial role in maintaining normal renal homeostasis as well as their capacity to modulate disease progression.
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Affiliation(s)
- Andrew E Libby
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, 3900 Reservoir Rd, Washington, DC, 20007, USA.
| | - Bryce Jones
- Department of Pharmacology and Physiology, Georgetown University, 3900 Reservoir Rd, Washington, DC, 20007, USA.
| | - Isabel Lopez-Santiago
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, 3900 Reservoir Rd, Washington, DC, 20007, USA.
| | - Emma Rowland
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, 3900 Reservoir Rd, Washington, DC, 20007, USA.
| | - Moshe Levi
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, 3900 Reservoir Rd, Washington, DC, 20007, USA.
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Teshome G, Ambachew S, Fasil A, Abebe M. Efficacy of Glucagon-Like Peptide-1 Analogs in Nonalcoholic Fatty Liver Disease: A Systematic Review. Hepat Med 2020; 12:139-151. [PMID: 33061687 PMCID: PMC7522518 DOI: 10.2147/hmer.s265631] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 09/01/2020] [Indexed: 12/13/2022] Open
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. It is believed to be the hepatic manifestation of the metabolic syndrome. Many treatment approaches have been suggested so far, and several types of studies have been done to find treatment for NAFLD, the most promising of which are those with lifestyle interventions. Objective The aim of this systematic review was to evaluate the efficacy and safety of glucagon-like peptide-1 (GLP-1) analogs on the management of NAFLD. Methods The PubMed, MEDLINE, and Cochrane Central Library were searched to identify randomized controlled trials, single arm trials, and cohorts that compared GLP-1 analogs with a control treatment or baseline values with respect to efficacy and safety in patients living with NAFLD. The key outcomes were a change in serum transaminase, resolution of disease status measured by imaging or histological techniques, improvement in insulin resistance, and reduction in body weight. Results Initial searching retrieved 201 peer-reviewed articles and abstracts. Ten studies met all inclusion criteria. The review included a total of 590 participants with NAFLD. Following administration of GLP-1 analogs, a decrease in serum transaminases, improvement in liver histology and insulin resistance, and a reduction in body weight were observed. Compared with baseline, body weight, alanine aminotransferase, aspartate aminotransferase, and gamma glutamyltransferase were decreased by 5.5%, 59.5%, 52.8%, and 44.8%, respectively, due to GLP-1. Likewise, a reduction of proinflammatory cytokines and fibrosis markers and an enhancement of protective adipokines were observed in some of the studies. Conclusion The decrease in a key biochemical marker of liver injury following treatment with GLP-1 analogs, as well as improvements in imaging and histology, suggests that these agents may be effective alternatives for managing NAFLD. Registration CRD42018087262.
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Affiliation(s)
- Getnet Teshome
- University of Gondar Comprehensive Specialized Hospital, University of Gondar, Gondar, Amhara, Ethiopia
| | - Sintayehu Ambachew
- Department of Clinical Chemistry, University of Gondar, Gondar, Amhara, Ethiopia
| | - Alebachew Fasil
- Department of Clinical Chemistry, University of Gondar, Gondar, Amhara, Ethiopia
| | - Molla Abebe
- Department of Clinical Chemistry, University of Gondar, Gondar, Amhara, Ethiopia
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18
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Kinoshita T, Shimoda M, Nakashima K, Fushimi Y, Hirata Y, Tanabe A, Tatsumi F, Hirukawa H, Sanada J, Kohara K, Irie S, Kimura T, Nakamura Y, Nishioka M, Obata A, Nakanishi S, Mune T, Kaku K, Kaneto H. Comparison of the effects of three kinds of glucose-lowering drugs on non-alcoholic fatty liver disease in patients with type 2 diabetes: A randomized, open-label, three-arm, active control study. J Diabetes Investig 2020; 11:1612-1622. [PMID: 32329963 PMCID: PMC7610105 DOI: 10.1111/jdi.13279] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 03/13/2020] [Accepted: 04/12/2020] [Indexed: 12/14/2022] Open
Abstract
Aims/Introduction Non‐alcoholic fatty liver disease (NAFLD) is often observed in individuals with type 2 diabetes mellitus, and it is known that the presence of type 2 diabetes mellitus leads to the aggravation of NAFLD. The aim of this study was to compare the possible effects of three kinds of oral hypoglycemic agents on NAFLD in individuals with type 2 diabetes mellitus. Materials and Methods We carried out a prospective clinical trial (a randomized and open‐label study) in patients with type 2 diabetes mellitus and NAFLD. A total of 98 patients were randomly allocated either to the dapagliflozin (n = 32), pioglitazone (n = 33) or glimepiride (n = 33) group, and the patients took these drugs for 28 weeks. The primary end‐point was the change of the liver‐to‐spleen ratio on abdominal computed tomography. Results There was no difference in baseline clinical characteristics among the three groups. Dapagliflozin, pioglitazone and glimepiride ameliorated hyperglycemia similarly. Bodyweight and visceral fat area were significantly decreased only in the dapagliflozin group. Serum adiponectin levels were markedly increased in the pioglitazone group compared with the other two groups. Dapagliflozin and pioglitazone, but not glimepiride, significantly increased the liver‐to‐spleen ratio, and the effects of dapagliflozin and pioglitazone on the liver‐to‐spleen ratio were comparable. Conclusions The present study showed that the decrease of visceral fat area and the increase of adiponectin level contributed to the improvement of NAFLD in patients with type 2 diabetes mellitus. Furthermore, dapagliflozin and pioglitazone exerted equivalent beneficial effects on NAFLD in patients with type 2 diabetes mellitus, although it seemed that these two drugs had different mechanisms of action.
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Affiliation(s)
- Tomoe Kinoshita
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Masashi Shimoda
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Koji Nakashima
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Yoshiro Fushimi
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Yurie Hirata
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Akihito Tanabe
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Fuminori Tatsumi
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Hidenori Hirukawa
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Junpei Sanada
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Kenji Kohara
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Shintaro Irie
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Tomohiko Kimura
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Yoshiko Nakamura
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Momoyo Nishioka
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Atsushi Obata
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Shuhei Nakanishi
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Tomoatsu Mune
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Kohei Kaku
- Kawasaki Medical School, Kurashiki, Japan
| | - Hideaki Kaneto
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
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19
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Lonardo A, Ballestri S. Perspectives of nonalcoholic fatty liver disease research: a personal point of view. EXPLORATION OF MEDICINE 2020; 1:85-107. [DOI: 10.37349/emed.2020.00007] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 04/27/2020] [Indexed: 01/04/2025] Open
Abstract
Rational government of patient fluxes from primary care to hepatology clinic is a priority of nonalcoholic fatty liver disease (NAFLD) research. Estimating pre-test probability of disease, risk of fibrosis progression, and exclusion of competing causes of liver disease must be addressed. Here we propose a novel taxonomic classification of NAFLD based on hepatic, pathogenic and systemic features of disease in the individual patient. The variable course of disease in any given patient remains a clinical enigma. Therefore, future studies will have to better characterize the role of genetic polymorphisms, family and personal history, diet, alcohol, physical activity and drugs as modifiers of the course of disease and clues to the early diagnosis of hepatocellular carcinoma. A better understanding of these, together with a taxonomic diagnosis, may prompt a more accurate personalization of care. For example, understanding the putative role of psycho-depression in NAFLD promises to revolutionize disease management in a proportion of cases. Similarly, sex differences in outcome and response to treatment are insufficiently characterized. More studies are awaited regarding those forms of NAFLD which occur secondary to endocrine derangements. The intersections between NAFLD and the lung must better be defined. These include the bi-directional associations of NAFLD and chronic obstructive pulmonary disease and sleep apnoea syndrome, as well as the totally unexplored chapter of NAFLD and coronavirus disease 2019 (COVID-19). Finally, the therapeutic roles of intermittent fasting and anticoagulation must be assessed. In conclusion, over the last 20 years, NAFLD has taught us a lot regarding the pathogenic importance of insulin resistance, the limitations of correcting this in the treatment of NAFLD, the root causes of diabetes and the metabolic syndrome, sex differences in disease and the role of nuclear receptors. However, the overwhelming COVID-19 pandemic is now expected to reset the priorities of public health.
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Affiliation(s)
- Amedeo Lonardo
- Azienda Ospedaliero-Universitaria, Ospedale Civile di Baggiovara, 41125 Modena, Italy
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20
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Bertasso IM, Pietrobon CB, Lopes BP, Peixoto TC, Soares PN, Oliveira E, Manhães AC, Bonfleur ML, Balbo SL, Cabral SS, Gabriel Kluck GE, Atella GC, Gaspar de Moura E, Lisboa PC. Programming of hepatic lipid metabolism in a rat model of postnatal nicotine exposure - Sex-related differences. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2020; 258:113781. [PMID: 31864076 DOI: 10.1016/j.envpol.2019.113781] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 12/04/2019] [Accepted: 12/08/2019] [Indexed: 06/10/2023]
Abstract
Maternal nicotine exposure during lactation induces liver damage in adult male rats. However, the mechanism in males is unknown and females have not been tested. Here, we determined the liver lipid composition and lipogenic enzymes in male and female offspring at two ages in a model of postnatal nicotine exposure. Osmotic minipumps were implanted in lactating Wistar rat dams at postnatal day (PND) 2 to release 6 mg/kg/day of nicotine (NIC group) or saline (CON group) for 14 days. Offspring received a standard diet from weaning until euthanasia at PND120 (1 pup/litter/sex) or PND180 (2 pups/litter/sex). At PND120, NIC males showed lower plasma triglycerides (TG), steatosis degree 1, higher hepatic cholesterol (CHOL) ester, free fatty acids, monoacylglycerol content as well as acetyl-coa carboxylase-1 (ACC-1) and fatty acid synthase (FAS) protein expression in the liver compared to CON males. At this age, NIC females had preserved hepatocytes architecture, higher plasma CHOL, higher CHOL ester and lower total CHOL content in the liver compared to CON females. At PND180, NIC males showed steatosis degrees 1 and 2, higher TG, lower free fatty acids and total CHOL content in the liver and an increase in ACC-1 hepatic protein expression. NIC females had higher plasma TG and CHOL levels, no change in hepatic morphology, lower CHOL ester and free fatty acids in the liver, which also showed higher total ACC-1 and FAS protein expression. Maternal nicotine exposure induces long-term liver dysfunction, with an alteration in hepatic cytoarchitecture that was aggravated with age in males. Concerning females, despite unchanged hepatic cytoarchitecture, lipid metabolism was compromised, which deserves further attention.
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Affiliation(s)
- Iala Milene Bertasso
- Laboratory of Endocrine Physiology, Biology Institute, State University of Rio de Janeiro, RJ, Brazil
| | - Carla Bruna Pietrobon
- Laboratory of Endocrine Physiology, Biology Institute, State University of Rio de Janeiro, RJ, Brazil
| | - Bruna Pereira Lopes
- Laboratory of Endocrine Physiology, Biology Institute, State University of Rio de Janeiro, RJ, Brazil
| | - Thamara Cherem Peixoto
- Laboratory of Endocrine Physiology, Biology Institute, State University of Rio de Janeiro, RJ, Brazil
| | - Patrícia Novaes Soares
- Laboratory of Endocrine Physiology, Biology Institute, State University of Rio de Janeiro, RJ, Brazil
| | - Elaine Oliveira
- Laboratory of Endocrine Physiology, Biology Institute, State University of Rio de Janeiro, RJ, Brazil
| | - Alex Christian Manhães
- Laboratory of Neurophysiology, Biology Institute, State University of Rio de Janeiro, RJ, Brazil
| | - Maria Lucia Bonfleur
- Laboratory of Endocrine Physiology and Metabolism, Center of Biological and Health Sciences, Western Paraná State University, Cascavel, PR, Brazil
| | - Sandra Lucinei Balbo
- Laboratory of Endocrine Physiology and Metabolism, Center of Biological and Health Sciences, Western Paraná State University, Cascavel, PR, Brazil
| | - Suellen Silva Cabral
- Laboratory of Lipids and Lipoprotein Biochemistry, Biochemistry Institute of Federal University of Rio de Janeiro, RJ, Brazil
| | - George Eduardo Gabriel Kluck
- Laboratory of Lipids and Lipoprotein Biochemistry, Biochemistry Institute of Federal University of Rio de Janeiro, RJ, Brazil
| | - Georgia Correa Atella
- Laboratory of Lipids and Lipoprotein Biochemistry, Biochemistry Institute of Federal University of Rio de Janeiro, RJ, Brazil
| | - Egberto Gaspar de Moura
- Laboratory of Endocrine Physiology, Biology Institute, State University of Rio de Janeiro, RJ, Brazil
| | - Patrícia Cristina Lisboa
- Laboratory of Endocrine Physiology, Biology Institute, State University of Rio de Janeiro, RJ, Brazil.
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21
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Liu J, Tan F, Liu X, Yi R, Zhao X. Grape skin fermentation by Lactobacillus fermentum CQPC04 has anti-oxidative effects on human embryonic kidney cells and apoptosis-promoting effects on human hepatoma cells. RSC Adv 2020; 10:4607-4620. [PMID: 35495273 PMCID: PMC9049054 DOI: 10.1039/c9ra09863a] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 01/17/2020] [Indexed: 12/13/2022] Open
Abstract
Studies on the antioxidant effects of grapes have attracted increasing interest. We used Lactobacillus fermentum CQPC04 to ferment grape skins. Components of the fermentation solution were separated and identified via high-performance liquid chromatography, and polyphenol compounds, including resveratrol and epicatechin, were isolated and identified from the fermentation solution. The major fermentation production components were assessed for their antioxidative abilities when administered under H2O2-induced oxidative damage in cell culture models. The fermentation solution significantly reduced oxidative damage, increased the expressions of the superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and GSH-peroxidase (GSH-Px) antioxidant genes and proteins in human embryonic kidney (293T) cells, stimulated the indices of total antioxidant capacity (T-AOC), SOD, CAT, GSH, and GSH-Px, and inhibited the indices of lactate dehydrogenase (LDH), malondialdehyde (MDA), and nitric oxide (NO), and the fermentation solution alleviated the increase in glutathione oxidized (GSSG) caused by oxidative damage, and the ratio of GSH/GSSG was up-regulated compared to the damage group. The fermentation solution also accelerated Human hepatoma (HepG2) cell death. Applying the fermentation solution to HepG2 cells significantly altered the cell morphology. HepG2 cell apoptosis and cell cycles were detected via flow cytometry. The fermentation solution promoted the apoptotic rate, and more cells were retained in the G2 phase, which prevented cells from further dividing. In the fermented group, the mRNA expression levels of Bcl-2, cox-2, PCNA, CD1, C-myc, CDK4, NF-κB and pRb1 were significantly decreased, and the expression levels of Caspase-3, Caspase-7, Caspase-8, Caspase-9, p53, TGF-β, and p21 were higher than those in the normal group. Phospho-NF-κB (p65), Bax and Caspase-8 protein expression increased, and NF-κB (p65) protein expression decreased. Protein expression levels also promoted apoptosis. Fermented grape skin solution is bioavailable in vitro and may help prevent oxidation and cancer cell proliferation.
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Affiliation(s)
- Jia Liu
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education Chongqing 400067 China +86-23-6265-3650
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education Chongqing 400067 China
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education Chongqing 400067 China
| | - Fang Tan
- Department of Public Health, Our Lady of Fatima University Valenzuela 838 Philippines
| | - Xinhong Liu
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education Chongqing 400067 China +86-23-6265-3650
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education Chongqing 400067 China
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education Chongqing 400067 China
- College of Biological and Chemical Engineering, Chongqing University of Education Chongqing 400067 China
| | - Ruokun Yi
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education Chongqing 400067 China +86-23-6265-3650
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education Chongqing 400067 China
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education Chongqing 400067 China
| | - Xin Zhao
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education Chongqing 400067 China +86-23-6265-3650
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education Chongqing 400067 China
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education Chongqing 400067 China
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22
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Liu J, Tan F, Liu X, Yi R, Zhao X. Exploring the Antioxidant Effects and Periodic Regulation of Cancer Cells by Polyphenols Produced by the Fermentation of Grape Skin by Lactobacillus plantarum KFY02. Biomolecules 2019; 9:E575. [PMID: 31590429 PMCID: PMC6843798 DOI: 10.3390/biom9100575] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 09/29/2019] [Accepted: 10/04/2019] [Indexed: 01/08/2023] Open
Abstract
Lactobacillus plantarum KFY02 (LP-KFY02) was isolated from naturally fermented yoghurt in Xinjiang. We previously demonstrated that LP-KFY02 has good biological activity in vitro. In this study, LP-KFY02 was used to ferment grape skin, and the LP-KFY02 fermented grape skin extract solution (KFSE) was examined for its antioxidant ability in a human embryonic kidney (293T) cell oxidative damage model caused by H2O2 and its inhibitory effect on human hepatoma (HepG2) cells. The results showed that KFSE reduced the degree of oxidative damage in 293T cells, increased the relevant expression levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and GSH-peroxidase (GSH-Px), and total antioxidant capacity (T-AOC), and decreased the expression levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), and nitric oxide (NO). The expression of genes and proteins of SOD, CAT, GSH, and GSH-Px was up-regulated. In addition, KFSE-induced growth inhibition appeared to be through induction of cell-cycle arrest. This induction was accompanied by a reduction in the expression of cell-cycle genes, such as cyclin-D1 and CDK4. In addition, KFSE induced gene expression of p21, the apoptosis gene wild-type p53 and the caspase family. At the protein expression level, Bax and Caspase-8 were up-regulated, and the inflammatory marker Nuclear Factor Kappa-B (NF-κB) was down-regulated. The fermentation solution polyphenols were separated and identified as epicatechin gallate, coumarin, new chlorogenic acid, rutin, resveratrol, chlorogenic acid, rosmarinic acid, etc. by HPLC. Overall, these results demonstrate that KFSE significantly attenuated oxidative damage in 293T cells and inhibited tumor growth in HepG2 cancer cells, induces cell-cycle arrest and affects proteins involved in cell-cycle regulation and proliferation. This suggests that KFSE may also be explored as a neo-adjuvant to expansion of hepatoma.
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Affiliation(s)
- Jia Liu
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing 400067, China.
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing 400067, China.
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing 400067, China.
| | - Fang Tan
- Department of Public Health, Our Lady of Fatima University, Valenzuela 838, Philippines.
| | - Xinhong Liu
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing 400067, China.
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing 400067, China.
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing 400067, China.
- College of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, China.
| | - Ruokun Yi
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing 400067, China.
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing 400067, China.
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing 400067, China.
| | - Xin Zhao
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing 400067, China.
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing 400067, China.
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing 400067, China.
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Liu B, Zhang J, Sun P, Yi R, Han X, Zhao X. Raw Bowl Tea (Tuocha) Polyphenol Prevention of Nonalcoholic Fatty Liver Disease by Regulating Intestinal Function in Mice. Biomolecules 2019; 9:biom9090435. [PMID: 31480575 PMCID: PMC6770140 DOI: 10.3390/biom9090435] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 08/28/2019] [Accepted: 08/30/2019] [Indexed: 02/07/2023] Open
Abstract
A high-fat diet-induced C57BL/6N mouse model of non-alcoholic fatty liver disease (NAFLD) was established. The effect and mechanism of Raw Bowl Tea polyphenols (RBTP) on preventing NAFLD via regulating intestinal function were observed. The serum, liver, epididymis, small intestine tissues, and feces of mice were examined by biochemical and molecular biological methods, and the composition of RBTP was analyzed by HPLC assay. The results showed that RBTP could effectively reduce the body weight, liver weight, and liver index of NAFLD mice. The serum effects of RBTP were: (1) decreases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP), total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), D-lactate (D-LA), diamine oxidase (DAO), lipopolysaccharide (LPS), and an increase of high density lipoprotein cholesterol (HDL-C) levels; (2) a decrease of inflammatory cytokines such as interleukin 1 beta (IL-1β), interleukin 4 (IL-4), interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-α), and interferon gamma (INF-γ); (3) a decrease the reactive oxygen species (ROS) level in liver tissue; and (4) alleviation of pathological injuries of liver, epididymis, and small intestinal tissues caused by NAFLD and protection of body tissues. qPCR and Western blot results showed that RBTP could up-regulate the mRNA and protein expressions of LPL, PPAR-α, CYP7A1, and CPT1, and down-regulate PPAR-γ and C/EBP-α in the liver of NAFLD mice. In addition, RBTP up-regulated the expression of occludin and ZO-1, and down-regulated the expression of CD36 and TNF-α in the small intestines of NAFLD mice. Studies on mice feces showed that RBTP reduced the level of Firmicutes and increased the minimum levels of Bacteroides and Akkermansia, as well as reduced the proportion of Firmicutes/Bacteroides in the feces of NAFLD mice, which play a role in regulating intestinal microecology. Component analysis showed that RBTP contained seven polyphenolic compounds: Gallic acid, (-)-epigallocatechin, catechin, L-epicatechin, (-)-epigallocatechin gallate, (-)-gallocatechin gallate, and (-)-epicatechin gallate (ECG), and high levels of caffeine, (-)-epigallocatechin (EGC), and ECG. RBTP improved the intestinal environment of NAFLD mice with the contained active ingredients, thus playing a role in preventing NAFLD. The effect was positively correlated with the dose of 100 mg/kg, which was even better than that of the clinical drug bezafibrate.
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Affiliation(s)
- Bihui Liu
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing 400067, China
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing 400067, China
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing 400067, China
- College of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, China
| | - Jing Zhang
- Environment and Quality Inspection College, Chongqing Chemical Industry Vocational College, Chongqing 401228, China
| | - Peng Sun
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing 400067, China
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing 400067, China
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing 400067, China
- College of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, China
| | - Ruokun Yi
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing 400067, China
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing 400067, China
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing 400067, China
| | - Xiaoyan Han
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing 400067, China
- College of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, China
| | - Xin Zhao
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing 400067, China.
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing 400067, China.
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing 400067, China.
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Beyond the Scavenging of Reactive Oxygen Species (ROS): Direct Effect of Cerium Oxide Nanoparticles in Reducing Fatty Acids Content in an In Vitro Model of Hepatocellular Steatosis. Biomolecules 2019; 9:biom9090425. [PMID: 31470518 PMCID: PMC6770635 DOI: 10.3390/biom9090425] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 08/09/2019] [Accepted: 08/27/2019] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic accumulation of lipids. Antisteatotic effects of cerium oxide nanoparticles (CeO2NPs) have recently been shown in animal models of liver disease. However, it is unclear whether the activity of CeO2NPs is related solely to the decrease in oxidative stress or, in addition, they directly decrease liver fatty acid accumulation. To address this question, in this work, we used an in vitro model of hepatocellular steatosis, exposing HepG2 cells to oleic and palmitic acid. Cell uptake of CeO2NPs and their effect on oxidative stress and viability of hepatic cells cultured with H2O2 were also evaluated. Results show that CeO2NPs were uptaken by HepG2 cells and reduced oxidative stress and improved cell viability. Treatment with oleic and palmitic acid increased lipogenesis and the content of different fatty acids. CeO2NPs reduced palmitic and stearic acid and most fatty acids consisting of more than 18 carbon atoms. These effects were associated with significant changes in elongase and desaturase activity. In conclusion, CeO2NPs directly protected HepG2 cells from cell injury in oxidative stress conditions and reduced fatty acid content in steatotic conditions by inducing specific changes in fatty acid metabolism, thus showing potential in the treatment of NAFLD.
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Nascimbeni F, Pellegrini E, Lugari S, Mondelli A, Bursi S, Onfiani G, Carubbi F, Lonardo A. Statins and nonalcoholic fatty liver disease in the era of precision medicine: More friends than foes. Atherosclerosis 2019; 284:66-74. [PMID: 30875495 DOI: 10.1016/j.atherosclerosis.2019.02.028] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 02/26/2019] [Accepted: 02/27/2019] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of alcohol-like hepatic histological changes, which occur in the absence of any competing causes of chronic liver disease, notably including significant alcohol consumption. A close and bi-directional relationship links NAFLD with the metabolic syndrome (MetS), and concurrent MetS will hasten the progression to more severe forms of NAFLD, including cirrhosis and hepatocellular carcinoma (HCC). Patients with NAFLD will typically exhibit atherogenic dyslipidemia and increased cardiovascular risk (CVR). Statins are among the most widely prescribed lipid-lowering drugs. Their use has historically been hampered, in individuals with liver disease, owing to the fear of hepatotoxicity. However, studies suggest that statins are not only effective in reducing cardiovascular events, but may also exert multiple beneficial effects on the liver. CVR in those with NAFLD has extensively been covered by our group and others. This updated clinical narrative review will critically examine the effects of statins on the pathogenesis of NAFLD, including the key elementary pathological lesions of NAFLD, i.e. steatosis, inflammation and fibrosis, and its liver-related complications, i.e. cirrhosis, portal hypertension and HCC.
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Affiliation(s)
- Fabio Nascimbeni
- Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy.
| | - Elisa Pellegrini
- Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
| | - Simonetta Lugari
- Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena and University of Modena and Reggio Emilia, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
| | - Alberto Mondelli
- Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena and University of Modena and Reggio Emilia, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
| | - Serena Bursi
- Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena and University of Modena and Reggio Emilia, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
| | - Giovanna Onfiani
- Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena and University of Modena and Reggio Emilia, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
| | - Francesca Carubbi
- Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena and University of Modena and Reggio Emilia, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
| | - Amedeo Lonardo
- Operating Unit of Internal and Metabolic Medicine, Azienda Ospedaliero-Universitaria of Modena, Civil Hospital of Baggiovara, Via Giardini 1355, 41126, Modena, Italy
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Lonardo A, Lugari S, Ballestri S, Nascimbeni F, Baldelli E, Maurantonio M. A round trip from nonalcoholic fatty liver disease to diabetes: molecular targets to the rescue? Acta Diabetol 2019; 56:385-396. [PMID: 30519965 DOI: 10.1007/s00592-018-1266-0] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 11/27/2018] [Indexed: 02/07/2023]
Abstract
Evidence suggests a close relationship between nonalcoholic fatty liver disease (NAFLD) and type two diabetes (T2D). On the grounds of prevalence of disease, both conditions account for a significant financial cost for health care systems and individuals. Aim of this review article is to explore the epidemiological basis and the putative molecular mechanisms underlying the association of NAFLD with T2D. Epidemiological studies have shown that NAFLD is associated to the development of incident T2D and either reversal or improvement of NAFLD will result into decreased risk of developing incident T2D. On the other side of the coin data have shown that T2D will worsen the course of NAFLD doubling the risk of disease progression (i.e. evolution from simple steatosis to advanced fibrosis, cirrhosis, hepatocellular carcinoma, liver transplant and death). Conversely, NAFLD will contribute to metabolic decompensation of T2D. The pathogenesis of T2D in NAFLD patients may be mediated by several hepatokines impairing metabolic control. Among these, Fetuin-B, which causes glucose intolerance and is increased in patients with T2D and NAFLD with fibrosis is one of the most promising. T2D may affect the progression of NAFLD by acting at different levels of the pathogenic cascade involving gut microbiota and expanded, inflamed, dysfunctional adipose tissue. In conclusion, T2D and NAFLD are mutually, closely and bi-directionally associated. An improved understanding of molecular pathogenesis underlying this bi-directional association may allow us to be able to prevent the development of T2D by halting the progression of NAFLD.
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Affiliation(s)
- Amedeo Lonardo
- Azienda Ospedaliero-Universitaria Modena, UO di Medicina Metabolica, Ospedale Civile di Baggiovara, Via Giardini 1135, 41125, Modena, Italy.
| | - Simonetta Lugari
- Università di Modena e Reggio Emilia, via del Pozzo, 71, 41124, Modena, Italy
| | - Stefano Ballestri
- Azienda USL di Modena, Ospedale Di Pavullo, UO di Medicina, Pavullo (Mo), Italy
| | - Fabio Nascimbeni
- Azienda Ospedaliero-Universitaria Modena, UO di Medicina Metabolica, Ospedale Civile di Baggiovara, Via Giardini 1135, 41125, Modena, Italy
| | - Enrica Baldelli
- Università di Modena e Reggio Emilia, via del Pozzo, 71, 41124, Modena, Italy
| | - Mauro Maurantonio
- Azienda Ospedaliero-Universitaria Modena, UO di Medicina Metabolica, Ospedale Civile di Baggiovara, Via Giardini 1135, 41125, Modena, Italy
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Cocci P, Mosconi G, Palermo FA. Changes in expression of microRNA potentially targeting key regulators of lipid metabolism in primary gilthead sea bream hepatocytes exposed to phthalates or flame retardants. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2019; 209:81-90. [PMID: 30753973 DOI: 10.1016/j.aquatox.2019.02.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 02/01/2019] [Accepted: 02/02/2019] [Indexed: 06/09/2023]
Abstract
Metabolism disrupting chemicals (MDCs) belong to the group of endocrine-disrupting chemicals (EDCs) and are known to affect endocrine and metabolic functions of liver. There is growing evidence that MDCs may also act modulating the expression levels of micro ribonucleic acids (miRNAs) and thus affecting post-transcriptional expression of hundreds of target genes. Herein, we used a gilthead sea bream in vitro hepatocyte model for analyzing the effects of an exposure to phthalates (i.e. DiDP) or flame retardants (i.e.TMCP) on the expression levels of three miRNAs (i.e. MiR133, MiR29 and MiR199a) selected on the basis of their regulatory roles in signaling pathways related to lipid metabolism. Following computational identification of genes that are regulated by the selected miRNAs, we identified six miRNA targets to be tested in differential gene expression analysis. To determine whether lipid metabolism was altered we have also measured the intracellular total cholesterol and triglyceride levels. The results of our study show that DiDP/TMCP exposure leads to a general decrease in the expression profiles of each miRNA leading to a corresponding upregulation of almost all their putative targets. In addition, these findings were also associated to a corresponding increased hepatocellular lipid content. The present study thus contributes to support the importance of these small molecules in regulating MDC-induced expression of genes associated with hepatic lipid metabolism and highlights the need for more toxicological studies examining miRNAs transcriptional regulatory networks controlling metabolic alterations in fish.
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Affiliation(s)
- Paolo Cocci
- School of Biosciences and Veterinary Medicine, University of Camerino, Via Gentile III Da Varano, I-62032 Camerino (MC), Italy
| | - Gilberto Mosconi
- School of Biosciences and Veterinary Medicine, University of Camerino, Via Gentile III Da Varano, I-62032 Camerino (MC), Italy
| | - Francesco Alessandro Palermo
- School of Biosciences and Veterinary Medicine, University of Camerino, Via Gentile III Da Varano, I-62032 Camerino (MC), Italy.
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Buerger AN, Schmidt J, Chase A, Paixao C, Patel TN, Brumback BA, Kane AS, Martyniuk CJ, Bisesi JH. Examining the responses of the zebrafish (Danio rerio) gastrointestinal system to the suspected obesogen diethylhexyl phthalate. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2019; 245:1086-1094. [PMID: 30682743 DOI: 10.1016/j.envpol.2018.11.032] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 10/26/2018] [Accepted: 11/09/2018] [Indexed: 06/09/2023]
Abstract
Epidemiological evidence suggests that phthalate plasticizers may act as "obesogens", which are chemicals that exacerbate obesity. The gastrointestinal (GI) system is the primary exposure route for phthalates, however, the relationship between phthalate-driven perturbations of GI system functions that can influence obesity has yet to be examined. To address this knowledge gap, we exposed Danio rerio (zebrafish) for 60 days to either (1) Control feeding (5 mg/fish/day), (2) Overfeeding (20 mg/fish/day) or (3) Overfeeding with diethyl-hexyl phthalate (DEHP) (20 mg/fish/day with 3 mg/kg DEHP). After 60 days, Overfed and Overfed + DEHP zebrafish had elevated body mass, and hepatosomatic and gonadosomatic indices. RNAseq analysis of the GI revealed enrichment of gene networks related to lipid metabolism in the Overfed + DEHP group. Many of the enriched networks were under transcriptional control of peroxisome proliferator activated receptor alpha (pparα), a known modulator of lipid metabolism, immune function, and GI function. Real-time PCR confirmed that pparα was overexpressed in the Overfed + DEHP zebrafish, further revealing a pathway by which DEHP may influence lipid metabolism via the GI. These data increase our understanding of phthalate-driven effects on GI function and lipid metabolism, identifying gut-specific gene networks that may drive phthalate-exacerbated obesity.
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Affiliation(s)
- Amanda N Buerger
- Department of Environmental and Global Health, University of Florida, Gainesville, FL, 32611, USA; Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL, 32611, USA
| | - Jordan Schmidt
- Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL, 32611, USA; Department of Physiological Sciences, UF Genetics Institute, University of Florida, Gainesville, FL, 32611, USA
| | - Amanda Chase
- Department of Environmental and Global Health, University of Florida, Gainesville, FL, 32611, USA; Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL, 32611, USA
| | - Carla Paixao
- Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL, 32611, USA; Department of Physiological Sciences, UF Genetics Institute, University of Florida, Gainesville, FL, 32611, USA
| | - Tejas N Patel
- Department of Environmental and Global Health, University of Florida, Gainesville, FL, 32611, USA; Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL, 32611, USA
| | - Babette A Brumback
- Department of Biostatistics, University of Florida, Gainesville, FL, 32611, USA
| | - Andrew S Kane
- Department of Environmental and Global Health, University of Florida, Gainesville, FL, 32611, USA; Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL, 32611, USA; Emerging Pathogens Institute, University of Florida, Gainesville, FL, 32611, USA
| | - Christopher J Martyniuk
- Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL, 32611, USA; Department of Physiological Sciences, UF Genetics Institute, University of Florida, Gainesville, FL, 32611, USA
| | - Joseph H Bisesi
- Department of Environmental and Global Health, University of Florida, Gainesville, FL, 32611, USA; Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL, 32611, USA.
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Zhang SS, Wang LY. Frontiers and prospects of pharmacotherapy for non-alcoholic fatty liver disease. Shijie Huaren Xiaohua Zazhi 2019; 27:73-79. [DOI: 10.11569/wcjd.v27.i2.73] [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] [Indexed: 02/06/2023] Open
Abstract
Although the prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing in recent years, acknowledged pharmacological intervention with obvious effectiveness specifically for NAFLD is still absent clinically. Currently, the mainstay treatment for patients suffering from NAFLD is life style modification including weight reduction and dietary regimen. However, sometimes these modalities do not work well, especially for patients with non-alcoholic steatohepatitis (NASH). Several medications, mainly targeting disease pathogenesis of NAFLD, have been investigated in clinical trials for treatment of NASH with promising results. At present, only pioglitazone acting as an insulin sensitizing agent and vitamin E as an anti-oxidant have been recommended for treatment of NASH by the American Association for the study of liver disease and European Association for study of the Liver. Lipid lowering agents including statins and fibrates, pentoxifylline, angiotensin receptor blockers, ursodeoxycholic acid, probiotics and synbiotics are current agents with beneficial effects for treatment of NASH but have not been approved yet due to the lack of strong evidence from available RCT trials in small populations. Several emerging medications aiming to treat NASH, such as obeticholic acid, liraglutide, elafibranor, cenicriviroc, aramchol, fibroblast growth factor (FGF)-21 or FGF-19 analogues, IMM-124e, orlistat, solithromycin, simtuzumab, GR-MD-02, remogliflozin etabonate, lipaglyn, SHP626 and PXS4728A, have been tested in clinical trials or are completing trials. Herein, current and upcoming pharmacotherapies targeting four main pathogenesis pathways including hepatic fat accumulation and the resultant metabolic stress, oxidative stress, involved gut microbiome disorders, and fibrotic process are reviewed.
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Affiliation(s)
- Shan-Shan Zhang
- Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, Guangdong Province, China
| | - Lai-You Wang
- Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, Guangdong Province, China
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Concurrent exercise improves insulin resistance and nonalcoholic fatty liver disease by upregulating PPAR-γ and genes involved in the beta-oxidation of fatty acids in ApoE-KO mice fed a high-fat diet. Lipids Health Dis 2019; 18:6. [PMID: 30611282 PMCID: PMC6320624 DOI: 10.1186/s12944-018-0933-z] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Accepted: 11/27/2018] [Indexed: 12/16/2022] Open
Abstract
Objective To emphasize the mechanism of concurrent exercise effect on lipid disorders in insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD). Materials and methods Twenty male ApoE knockout mice were randomly divided into two groups: HFD group (n = 10) fed a high fat diet, and HFDE group (n = 10) with high-fat diet intervention for 12 weeks and swimming exercise. Other ten healthy male C57BL/6 J mice were fed a normal diet, and included as control group. Retro-orbital blood samples were collected for biochemical analysis. Oil red O staining of liver tissues was performed to confirm the exercise effect. Western blotting was performed to evaluate the expressions of PPAR-γ, CPT-1, MCAD. Results The levels of TG, TC, LDL, FFA, FIN, FPG and Homa-IRI in the HFD group were significantly higher than ND group, while these were markedly decreased in the HFDE group compared with HFD group. The Oil Red O staining of liver samples further confirmed the exercise effect on the change of lipid deposition in the liver. Western blotting showed increased expressions of PPAR-γ, CPT-1, MCAD induced by high fat diet were significantly downregulated by exercise. Conclusion A concurrent 12-week exercise protocol alleviated the lipid metabolism disorders of IR and NAFLD, probably via PPAR-γ/CPT-1/MCAD signaling.
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Li C, Liu Q, Xie L. Suppressing NLRP2 expression accelerates hepatic steatosis: A mechanism involving inflammation and oxidative stress. Biochem Biophys Res Commun 2018; 507:22-29. [PMID: 30454891 DOI: 10.1016/j.bbrc.2018.10.132] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 10/22/2018] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation and inflammation in the liver, contributing to a broad spectrum of severe pathologies, such as metabolic syndrome and hepatocellular carcinoma. Presently, the pathogenesis that attributes to NAFLD has not been fully understood. NLRP2 has been shown to inhibit the NF-κB signaling, and thus may contribute to regulate the inflammatory response. However, its role in NAFLD is largely unclear. In the study, we found that NLRP2 was markedly decreased in liver tissues of individuals with severe steatosis, or in a genetic deficiency (ob/ob) mice. High fat diet (HFD) feeding also led to a significant reduction of NLRP2 in liver of mice. Then, the wild type (WT) and NLRP2 knockout (KO) mice were used to further explore the role of NLRP2 in the NAFLD progression. NLRP2 knockout mice exhibited severer metabolic syndrome and hepatic steatosis after HFD administration, as evidenced by the increased body weight, liver histological changes and lipid accumulation. Moreover, HFD feeding-induced inflammation was significantly accelerated by the loss of NLRP2, as evidenced by the increased expression of pro-inflammatory cytokines and activation of nuclear factor κB (NF-κB) pathway. In addition, oxidative stress triggered by HFD was further promoted by NLRP2 deletion through repressing NF-E2-related factor 2 (Nrf2) pathway. In vitro, we surprisingly found that promoting Nrf2 activation could attenuate NLRP2 knockout-accelerated inflammation and reactive oxygen species (ROS) generation. Therefore, our study indicated that NLRP2 might be a potential target for developing effective therapeutic strategy to prevent NAFLD progression.
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Affiliation(s)
- Chen Li
- Department of Gastroenterology, Xuzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Xuzhou, 221000, China
| | - Qing Liu
- Department of Oncology, Xuzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Xuzhou, 221000, China
| | - Liqun Xie
- Department of Traditional Chinese Medicine, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210009, China.
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Lugari S, Mantovani A, Nascimbeni F, Lonardo A. Hypothyroidism and nonalcoholic fatty liver disease - a chance association? Horm Mol Biol Clin Investig 2018; 41:/j/hmbci.2020.41.issue-1/hmbci-2018-0047/hmbci-2018-0047.xml. [PMID: 30367792 DOI: 10.1515/hmbci-2018-0047] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 09/11/2018] [Indexed: 02/07/2023]
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) defines the clinical-pathological spectrum of hepatic lipotoxicity, which may progress to hepatic fibrosis and its complications. Thyroid hormone is a master regulator of cell metabolism and body fat distribution. Whether hypothyroidism is associated or not with an increased risk of developing NAFLD and its fibrotic progression is both clinically and physiopathologically relevant. Indeed, answering this research question would carry major pathogenic and therapeutic implications. Method PubMed database was searched using relevant key-words such as hypothyroidism; NAFLD; nonalcoholic steatohepatitis; cirrhosis; hepatocellular carcinoma; epidemiology; pathogenesis; natural history. The epidemiological studies and the meta-analyses published so far were identified as well as those studies addressing the physiopathology underlying this association. Results Many observational studies have investigated the association between either subclinical or overt hypothyroidism and NAFLD. Data are conflicting: some original and meta-analytical studies demonstrated that hypothyroidism, (mainly subclinical hypothyroidism), was common, occurring in approximately 25% of individuals with imaging-defined or biopsy-proven NAFLD; other studies, however, failed to identify a significant association between hypothyroidism and NAFLD. Moreover, such an association is biologically plausible based on the specific physiopathological impact of thyroid hormone and thyroid stimulating hormone (TSH) on metabolism of hepatocytes and accumulation and distribution of body fat. Conclusions The findings from the present review support a significant association between primary hypothyroidism and risk of development and progression of NAFLD. However, further studies evaluating the relative importance of subclinical versus overt hypothyroidism as well as addressing the mechanisms underlying the association of hypothyroidism with NAFLD are eagerly awaited.
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Affiliation(s)
- Simonetta Lugari
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Fabio Nascimbeni
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Amedeo Lonardo
- Division of Internal Medicine, Department of Biomedical, Metabolic and Neural Sciences, Azienda Ospedaliero-Universitaria, Ospedale Civile di Baggiovara, Modena, Italy
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Athuluri-Divakar SK, Hoshida Y. Generic chemoprevention of hepatocellular carcinoma. Ann N Y Acad Sci 2018; 1440:23-35. [PMID: 30221358 DOI: 10.1111/nyas.13971] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 08/21/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023]
Abstract
Chronic fibrotic liver disease caused by viral or metabolic etiologies is a high-risk condition for developing hepatocellular carcinoma (HCC). Even after curative treatment of early-stage HCC tumor, the carcinogenic microenvironment persists in the remnant diseased liver and supports the development of de novo HCC tumors (de novo HCC recurrence). Therefore, prevention of HCC development in patients at risk of not only first-primary but also second-primary HCC tumors is theoretically the most impactful strategy to improve patient prognosis. However, no such therapy has been established to date. One major challenge is the identification of clinically relevant targets that can be achieved by utilizing the reverse-engineering strategy of chemoprevention discovery, which integrates omics information from clinical cohorts with completed follow-up for cancer development. Clinical and experimental studies have suggested etiology-specific and generic candidate HCC chemoprevention strategies, including statins, antidiabetic drugs, selective molecular targeted agents, and dietary and nutritional substances. Clinical testing of the candidate compounds can be cost-effectively performed by combining it with HCC risk biomarker evaluation to specify the target patient population most likely to benefit from the therapy. Nontoxic, generic agents will have broad clinical applicability across the diverse HCC etiologies and clinical contexts and are expected to substantially improve the still dismal prognosis of HCC.
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Affiliation(s)
- Sai Krishna Athuluri-Divakar
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Yujin Hoshida
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
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Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues. Mol Aspects Med 2018; 65:37-55. [PMID: 30213667 DOI: 10.1016/j.mam.2018.09.002] [Citation(s) in RCA: 746] [Impact Index Per Article: 106.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 09/05/2018] [Accepted: 09/07/2018] [Indexed: 02/06/2023]
Abstract
The progression of chronic liver diseases (CLD), irrespective of etiology, involves chronic parenchymal injury, persistent activation of inflammatory response as well as sustained activation of liver fibrogenesis and wound healing response. Liver fibrogenesis, is a dynamic, highly integrated molecular, cellular and tissue process responsible for driving the excess accumulation of extracellular matrix (ECM) components (i.e., liver fibrosis) sustained by an eterogeneous population of hepatic myofibroblasts (MFs). The process of liver fibrogenesis recognizes a number of common and etiology-independent mechanisms and events but it is also significantly influenced by the specific etiology, as also reflected by peculiar morphological patterns of liver fibrosis development. In this review we will analyze the most relevant established and/or emerging pathophysiological issues underlying CLD progression with a focus on the role of critical hepatic cell populations, mechanisms and signaling pathways involved, as they represent potential therapeutic targets, to finally analyze selected and relevant clinical issues.
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Deng W, Meng Z, Sun A, Yang Z. Pioglitazone suppresses inflammation and fibrosis in nonalcoholic fatty liver disease by down-regulating PDGF and TIMP-2: Evidence from in vitro study. Cancer Biomark 2018; 20:411-415. [PMID: 28946547 DOI: 10.3233/cbm-170157] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The prevalence of nonalcoholic fatty liver disease (NAFLD) has been increasing worldwide. Pioglitazone is a pharmacologic agonist of peroxisome proliferators-activated receptor-γ (PPAR-γ) that was reported to ameliorate hepatic steatosis and inflammatory changes. OBJECTIVE We aimed to evaluate the effects of pioglitazone in NAFLD and investigate the underlying mechanism by testing platelet derived growth factor (PDGF) and tissue inhibitory of metalloproteinase-2 (TIMP-2). METHODS A total of C57BL/6 wild-type mice were randomized to three groups, control group (NC, n= 60), high-fat control group (HF, n= 60), and pioglitazone treatment group (L,n= 60). Mice were administrated with high-fat diet to construct NAFLD model. Enzyme-linked immunosorbent assay (ELISA) was used to measure protein expression of PDGF and TIMP-2. Liver histology samples were stained with hematoxylin and eosin (H&E). RESULTS Upon pioglitazone treatment, the PDGF and TIMP-2 expression levels were decreased compared with high-fat diet-fed mice devoid of drug stimulation. Analysis of liver histology showed pioglitazone treatment could reduce steatosis and inflammatory changes, which was helpful to inhibit hepatic fibrosis in NAFLD mice. CONCLUSIONS The study showed pioglitazone might exert an inhibitory effect on hepatic inflammation and fibrosis in NAFLD. Moreover, this study provided novel evidence for the promising clinical application of pioglitazone in intervening NAFLD.
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Affiliation(s)
- Wen Deng
- Department of Cardiovascular Medicine, Yantaishan Hospital, Yantai 264000, Shandong, China.,Department of Cardiovascular Medicine, Yantaishan Hospital, Yantai 264000, Shandong, China
| | - Zimin Meng
- Department of Cardiovascular Medicine, Weihai Municipal Hospital, Weihai 264200, Shandong, China.,Department of Cardiovascular Medicine, Yantaishan Hospital, Yantai 264000, Shandong, China
| | - Aitao Sun
- Department of Digestive, Yantaishan Hospital, Yantai 264000, Shandong, China
| | - Zhihong Yang
- Department of Digestive, Yantaishan Hospital, Yantai 264000, Shandong, China
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Jaiswal B, Gupta A. Modulation of Nuclear Receptor Function by Chromatin Modifying Factor TIP60. Endocrinology 2018; 159:2199-2215. [PMID: 29420715 DOI: 10.1210/en.2017-03190] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 01/31/2018] [Indexed: 02/07/2023]
Abstract
Nuclear receptors (NRs) are transcription factors that bind to specific DNA sequences known as hormone response elements located upstream of their target genes. Transcriptional activity of NRs can be modulated by binding of the compatible ligand and transient interaction with cellular coregulators, functioning either as coactivators or as corepressors. Many coactivator proteins possess intrinsic histone acetyltransferase (HAT) activity that catalyzes the acetylation of specific lysine residues in histone tails and loosens the histone-DNA interaction, thereby facilitating access of transcriptional factors to the regulatory sequences of the DNA. Tat interactive protein 60 (TIP60), a member of the Mof-Ybf2-Sas2-TIP60 family of HAT protein, is a multifunctional coregulator that controls a number of physiological processes including apoptosis, DNA damage repair, and transcriptional regulation. Over the last two decades or so, TIP60 has been extensively studied for its role as NR coregulator, controlling various aspect of steroid receptor functions. The aim of this review is to summarize the findings on the role of TIP60 as a coregulator for different classes of NRs and its overall functional implications. We also discuss the latest studies linking TIP60 to NR-associated metabolic disorders and cancers for its potential use as a therapeutic drug target in future.
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Affiliation(s)
- Bharti Jaiswal
- Department of Life Sciences, Shiv Nadar University, Greater Noida, Uttar Pradesh, India
| | - Ashish Gupta
- Department of Life Sciences, Shiv Nadar University, Greater Noida, Uttar Pradesh, India
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Wang F, Wu Y, Xie X, Sun J, Chen W. Essential role of nuclear receptors for the evaluation of the benefits of bioactive herbal extracts on liver function. Pharmacotherapy 2018; 99:798-809. [DOI: 10.1016/j.biopha.2018.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 12/29/2017] [Accepted: 01/03/2018] [Indexed: 02/07/2023]
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Zang S, Chen J, Song Y, Bai L, Chen J, Chi X, He F, Sheng H, Wang J, Xie S, Xie W, Yang Y, Zhang J, Zheng M, Zou Z, Wang B, Shi J. Haptoglobin Genotype and Vitamin E Versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis in China: A Multicenter, Randomized, Placebo-Controlled Trial Design. Adv Ther 2018; 35:218-231. [PMID: 29411270 DOI: 10.1007/s12325-018-0670-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Vitamin E is one of the most promising agents for nonalcoholic steatohepatitis (NASH) treatment, and its drug responsiveness may be closely associated with haptoglobin (Hp) genotype. However, its efficacy and safety remain unknown in China. This clinical trial of vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis (VENS) is conducted to evaluate (a) the efficacy and safety of treatment with vitamin E softgel (300 mg/day) determined from standardized histologic scoring of liver biopsies, (b) whether treatment with vitamin E improves biochemical parameters, cytokines, anthropometric parameters, controlled attenuation parameter (CAP), and transient elastography (TE) values determined by Fibroscan and health-related quality of life (SF-36), (c) whether the efficacy of vitamin E treatment is associated with the Hp genotype in nondiabetic adults with NASH. METHODS VENS is a multicenter, randomized, double-masked, placebo parallel controlled trial to evaluate the efficacy and safety of treatment with vitamin E softgel in nondiabetic adults with NASH versus treatment with placebo in China. Liver biopsies are read by a pathological evaluation committee independently according to the NASH Clinical Research Network (CRN) scoring system. The NAFLD activity score (NAS) represents the sum of scores for steatosis, lobular inflammation, and hepatocyte ballooning. The definition of histologic improvement requires all three of the following criteria to be met: (a) either improvement in NAS by at least 2 points or post-treatment NAS score no higher than 3, (b) at least 1-point improvement in the score for ballooning, and (c) no worsening of fibrosis stages. We plan to recruit 120 biopsy-proven NASH patients from13 centers in China. Participants will be randomly assigned to groups treated with either with vitamin E (100 mg, tid) or placebo for 96 weeks then followed by 24 weeks of post-treatment observation. Biochemical parameters, cytokines, anthropometric parameters, CAP and TE values, Hp genotype, and several questionnaires will be collected as per the schedule. This protocol was approved by the Ethics Committee of Hangzhou Normal University Affiliated Hospital to ensure patients safety, and R&G Pharmastudies Co., Ltd. was established for monitoring the accumulated interim data to review efficacy and quality of data collection and overall study management. RESULTS As a preliminary study, a mobile phone application (app) for lifestyle modification and database recording ( http://laiyivens.365hy.com ) was exploited for every participant. The percentage of NAFLD patients with Hp 2-2 allele is much higher than that of Western patients (65.71% vs 36%, respectively), which suggests that the Chinese benefit more from vitamin E treatment. CONCLUSION VENS is the first randomized controlled trial (RCT) to evaluate the efficacy of Vitamin E in treating nondiabetic NASH patients in China. TRIAL REGISTRATION This study registered at https://clinicaltrials.gov (registration number: NCT02962297). FUNDING Zhejiang Medicine Co., Ltd.
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Affiliation(s)
- Shufei Zang
- Department of Endocrinology, Hangzhou Normal University Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Jin Chen
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yu Song
- Department of Endocrinology, Hangzhou Normal University Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Lang Bai
- West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jinjun Chen
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaoling Chi
- Guangdong Provincial Chinese Medicine Hospital, Guangzhou, Guangdong, China
| | - Fangping He
- The First Affiliated Hospital of Xinjiang Medical, Urumqi, Xinjiang, China
| | - Huiping Sheng
- General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Jing Wang
- Department of Hepatobiliary Disease, Affiliated Hospital of Traditional Chinese Medicine of Southwest Medical University, Luzhou, Sichuan, China
| | - Shilong Xie
- Zhejiang Medicine Co. Ltd, Hangzhou, Zhejiang, China
| | - Wen Xie
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yongfeng Yang
- The Second Hospital of Nanjing, Nanjing, Jiangsu, China
| | - Jing Zhang
- Beijing You An Hospital Capital Medical University, Beijing, China
| | - Minghua Zheng
- Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | | | - Bingyuan Wang
- The First Hospital of China Medical University, Shenyang, Liaoning, China.
| | - Junping Shi
- Department of Hepatology, Hangzhou Normal University Affiliated Hospital, Hangzhou, Zhejiang, China.
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease worldwide, and its clinical and economic burden will continue to grow with parallel increases in rates of obesity, diabetes, and the metabolic syndrome. Evolving understanding of the natural history of NAFLD suggests that these patients are at risk for disease progression to steatohepatitis, fibrosis, and cirrhosis. Recent studies also suggest that these patients are at elevated risk for cardiovascular-, malignancy-, and liver-related morbidity and mortality, although their risk for progression, decompensation, and hepatocellular carcinoma may be less than that of patients with alternative causes of chronic liver disease.
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Affiliation(s)
- Christina C Lindenmeyer
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue, Mail Code A30, Cleveland, OH 44195, USA
| | - Arthur J McCullough
- Department of Gastroenterology and Hepatology, Transplantation Center, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue, Mail Code A30, Cleveland, OH 44195, USA; Department of Pathobiology, Transplantation Center, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue, Mail Code A30, Cleveland, OH 44195, USA.
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Eshraghian A. Current and emerging pharmacological therapy for non-alcoholic fatty liver disease. World J Gastroenterol 2017; 23:7495-7504. [PMID: 29204050 PMCID: PMC5698243 DOI: 10.3748/wjg.v23.i42.7495] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 09/14/2017] [Accepted: 09/19/2017] [Indexed: 02/06/2023] Open
Abstract
The main treatment of patients with non-alcoholic fatty liver disease (NAFLD) is life style modification including weight reduction and dietary regimen. Majority of patients are safely treated with this management and pharmacologic interventions are not recommended. However, a subgroup of NAFLD patients with non-alcoholic steatohepatitis (NASH) who cannot achieve goals of life style modification may need pharmacological therapy. One major obstacle is measurement of histological outcome by liver biopsy which is an invasive method and is not recommended routinely in these patients. Several medications, mainly targeting baseline mechanism of NAFLD, have been investigated in clinical trials for treatment of NASH with promising results. At present, only pioglitazone acting as insulin sensitizing agent and vitamin E as an anti-oxidant have been recommended for treatment of NASH by international guidelines. Lipid lowering agents including statins and fibrates, pentoxifylline, angiotensin receptor blockers, ursodeoxycholic acid, probiotics and synbiotics are current agents with beneficial effects for treatment of NASH but have not been approved yet. Several emerging medications are in development for treatment of NASH. Obeticholic acid, liraglutide, elafibranor, cenicriviroc and aramchol have been tested in clinical trials or are completing trials. Here in, current and upcoming medications with promising results in clinical trial for treatment of NAFLD were reviewed.
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Affiliation(s)
- Ahad Eshraghian
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz 71937-11351, Iran
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Cannito S, Novo E, Parola M. Therapeutic pro-fibrogenic signaling pathways in fibroblasts. Adv Drug Deliv Rev 2017; 121:57-84. [PMID: 28578015 DOI: 10.1016/j.addr.2017.05.017] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 04/28/2017] [Accepted: 05/26/2017] [Indexed: 02/07/2023]
Abstract
Myofibroblasts (MFs) play a critical role in the progression of chronic inflammatory and fibroproliferative diseases in different tissues/organs, whatever the etiology. Fibrosis is preceded and sustained by persistent injury and inflammatory response in a profibrogenic scenario involving mutual interactions, operated by several mediators and pathways, of MFs and related precursor cells with innate immunity cells and virtually any cell type in a defined tissue. These interactions, mediators and related signaling pathways are critical in initiating and perpetuating the differentiation of precursor cells into MFs that in different tissues share peculiar traits and phenotypic responses, including the ability to proliferate, produce ECM components, migrate and contribute to the modulation of inflammatory response and tissue angiogenesis. Literature studies related to liver, lung and kidney fibrosis have outlined a number of MF-related core regulatory fibrogenic signaling pathways conserved across these different organs and potentially targetable in order to develop effective antifibrotic therapeutic strategies.
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Chen Z, Yu R, Xiong Y, Du F, Zhu S. A vicious circle between insulin resistance and inflammation in nonalcoholic fatty liver disease. Lipids Health Dis 2017; 16:203. [PMID: 29037210 PMCID: PMC5644081 DOI: 10.1186/s12944-017-0572-9] [Citation(s) in RCA: 214] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 09/20/2017] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of diseases, including simple steatosis, nonalcoholic steatohepatitis (NASH), liver cirrhosis and hepatocellular carcinoma. Lipotoxicity, insulin resistance (IR) and inflammation are involved in the disease process. Lipotoxicity promotes inflammation and IR, which in turn, increase adipocyte lipolysis and exacerbates lipotoxicity. Furthermore, IR and inflammation form a vicious circle, with each condition promoting the other and accelerating the development of NAFLD in the presence of lipotoxicity. As an integrator of inflammatory pathway networks, nuclear factor-kappa B (NF-κB) regulates expression of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and anti-inflammatory cytokines, such as adiponectin in NAFLD. In this review, the relationships between lipotoxicity, IR and inflammation in NAFLD are discussed, with particular emphasis on the inflammatory pathways.
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Affiliation(s)
- Zhonge Chen
- Medical Center of The Graduate School, Nanchang University, Nanchang, China
| | - Rong Yu
- Department of Endocrinology, Second Affliated Hospital, Nanchang University, Nanchang, China
| | - Ying Xiong
- Department of Gastroenterology, Second Affliated Hospital, Nanchang University, No. 1, Minde Road, Nanchang, 330006, China
| | - Fangteng Du
- Department of Gastroenterology, Second Affliated Hospital, Nanchang University, No. 1, Minde Road, Nanchang, 330006, China.
| | - Shuishan Zhu
- Department of Gastroenterology, Second Affliated Hospital, Nanchang University, No. 1, Minde Road, Nanchang, 330006, China.
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Saokaew S, Kanchanasuwan S, Apisarnthanarak P, Charoensak A, Charatcharoenwitthaya P, Phisalprapa P, Chaiyakunapruk N. Clinical risk scoring for predicting non-alcoholic fatty liver disease in metabolic syndrome patients (NAFLD-MS score). Liver Int 2017; 37:1535-1543. [PMID: 28294515 DOI: 10.1111/liv.13413] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 03/06/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) can progress from simple steatosis to hepatocellular carcinoma. None of tools have been developed specifically for high-risk patients. This study aimed to develop a simple risk scoring to predict NAFLD in patients with metabolic syndrome (MetS). METHODS A total of 509 patients with MetS were recruited. All were diagnosed by clinicians with ultrasonography-confirmed whether they were patients with NAFLD. Patients were randomly divided into derivation (n=400) and validation (n=109) cohort. To develop the risk score, clinical risk indicators measured at the time of recruitment were built by logistic regression. Regression coefficients were transformed into item scores and added up to a total score. A risk scoring scheme was developed from clinical predictors: BMI ≥25, AST/ALT ≥1, ALT ≥40, type 2 diabetes mellitus and central obesity. The scoring scheme was applied in validation cohort to test the performance. RESULTS The scheme explained, by area under the receiver operating characteristic curve (AuROC), 76.8% of being NAFLD with good calibration (Hosmer-Lemeshow χ2 =4.35; P=.629). The positive likelihood ratio of NAFLD in patients with low risk (scores below 3) and high risk (scores 5 and over) were 2.32 (95% CI: 1.90-2.82) and 7.77 (95% CI: 2.47-24.47) respectively. When applied in validation cohort, the score showed good performance with AuROC 76.7%, and illustrated 84%, and 100% certainty in low- and high-risk groups respectively. CONCLUSIONS A simple and non-invasive scoring scheme of five predictors provides good prediction indices for NAFLD in MetS patients. This scheme may help clinicians in order to take further appropriate action.
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Affiliation(s)
- Surasak Saokaew
- Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand.,School of Pharmacy, Monash University Malaysia, Selangor, Malaysia.,Center of Pharmaceutical Outcomes Research (CPOR), Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand
| | - Shada Kanchanasuwan
- Clinical and Administrative Pharmacy, The University of Georgia College of Pharmacy, Athens, GA, USA
| | - Piyaporn Apisarnthanarak
- Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Aphinya Charoensak
- Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Phunchai Charatcharoenwitthaya
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Pochamana Phisalprapa
- Division of Ambulatory Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Nathorn Chaiyakunapruk
- School of Pharmacy, Monash University Malaysia, Selangor, Malaysia.,Center of Pharmaceutical Outcomes Research (CPOR), Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand.,School of Pharmacy, University of Wisconsin, Madison, WI, USA.,School of Population Health, University of Queensland, Brisbane, Qld, Australia
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Singh S, Osna NA, Kharbanda KK. Treatment options for alcoholic and non-alcoholic fatty liver disease: A review. World J Gastroenterol 2017; 23:6549-6570. [PMID: 29085205 PMCID: PMC5643281 DOI: 10.3748/wjg.v23.i36.6549] [Citation(s) in RCA: 174] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Revised: 07/25/2017] [Accepted: 09/05/2017] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are serious health problems worldwide. These two diseases have similar pathological spectra, ranging from simple steatosis to hepatitis to cirrhosis and hepatocellular carcinoma. Although most people with excessive alcohol or calorie intake display abnormal fat accumulation in the liver (simple steatosis), a small percentage develops progressive liver disease. Despite extensive research on understanding the pathophysiology of both these diseases there are still no targeted therapies available. The treatment for ALD remains as it was 50 years ago: abstinence, nutritional support and corticosteroids (or pentoxifylline as an alternative if steroids are contraindicated). As for NAFLD, the treatment modality is mainly directed toward weight loss and co-morbidity management. Therefore, new pathophysiology directed therapies are urgently needed. However, the involvement of several inter-related pathways in the pathogenesis of these diseases suggests that a single therapeutic agent is unlikely to be an effective treatment strategy. Hence, a combination therapy towards multiple targets would eventually be required. In this review, we delineate the treatment options in ALD and NAFLD, including various new targeted therapies that are currently under investigation. We hope that soon we will be having an effective multi-therapeutic regimen for each disease.
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Affiliation(s)
- Sukhpreet Singh
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Biochemistry and Molecular Biology, Nebraska Medical Center, Omaha, NE 68198, United States
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Lonardo A, Nascimbeni F, Maurantonio M, Marrazzo A, Rinaldi L, Adinolfi LE. Nonalcoholic fatty liver disease: Evolving paradigms. World J Gastroenterol 2017; 23:6571-6592. [PMID: 29085206 PMCID: PMC5643282 DOI: 10.3748/wjg.v23.i36.6571] [Citation(s) in RCA: 132] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 08/21/2017] [Accepted: 09/05/2017] [Indexed: 02/06/2023] Open
Abstract
In the last years new evidence has accumulated on nonalcoholic fatty liver disease (NAFLD) challenging the paradigms that had been holding the scene over the previous 30 years. NAFLD has such an epidemic prevalence as to make it impossible to screen general population looking for NAFLD cases. Conversely, focusing on those cohorts of individuals exposed to the highest risk of NAFLD could be a more rational approach. NAFLD, which can be diagnosed with either non-invasive strategies or through liver biopsy, is a pathogenically complex and clinically heterogeneous disease. The existence of metabolic as opposed to genetic-associated disease, notably including "lean NAFLD" has recently been recognized. Moreover, NAFLD is a systemic condition, featuring metabolic, cardiovascular and (hepatic/extra-hepatic) cancer risk. Among the clinico-laboratory features of NAFLD we discuss hyperuricemia, insulin resistance, atherosclerosis, gallstones, psoriasis and selected endocrine derangements. NAFLD is a precursor of type 2 diabetes (T2D) and metabolic syndrome and progressive liver disease develops in T2D patients in whom the course of disease is worsened by NAFLD. Finally, lifestyle changes and drug treatment options to be implemented in the individual patient are also critically discussed. In conclusion, this review emphasizes the new concepts on clinical and pathogenic heterogeneity of NAFLD, a systemic disorder with a multifactorial pathogenesis and protean clinical manifestations. It is highly prevalent in certain cohorts of individuals who are thus potentially amenable to selective screening strategies, intensive follow-up schedules for early identification of liver-related and extrahepatic complications and in whom earlier and more aggressive treatment schedules should be carried out whenever possible.
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Affiliation(s)
- Amedeo Lonardo
- Azienda Ospedaliero-Universitaria di Modena, Ospedale Civile di Baggiovara, 41126 Modena, Italy
| | - Fabio Nascimbeni
- Azienda Ospedaliero-Universitaria di Modena, Ospedale Civile di Baggiovara, 41126 Modena, Italy
- University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Mauro Maurantonio
- Azienda Ospedaliero-Universitaria di Modena, Ospedale Civile di Baggiovara, 41126 Modena, Italy
| | - Alessandra Marrazzo
- Azienda Ospedaliero-Universitaria di Modena, Ospedale Civile di Baggiovara, 41126 Modena, Italy
- University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Luca Rinaldi
- Department of Medical, Surgical, Neurological, Geriatric, and Metabolic Sciences, University of Campania “Luigi Vanvitelli”, 80100 Naples, Italy
| | - Luigi Elio Adinolfi
- Department of Medical, Surgical, Neurological, Geriatric, and Metabolic Sciences, University of Campania “Luigi Vanvitelli”, 80100 Naples, Italy
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Lonardo A, Targher G. NAFLD: Is There Anything New under the Sun? Int J Mol Sci 2017; 18:1955. [PMID: 28895919 PMCID: PMC5618604 DOI: 10.3390/ijms18091955] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 09/10/2017] [Accepted: 09/10/2017] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is an "umbrella" definition that encompasses a spectrum of histological liver changes ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with/without fibrosis, "cryptogenic" cirrhosis, and hepatocellular carcinoma (HCC), occurring in a dysmetabolic milieu, though in the absence of excessive alcohol consumption and other competing etiologies of chronic liver disease [1].[...].
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Affiliation(s)
- Amedeo Lonardo
- Division of Internal Medicine, Department of Biomedical, Metabolic and Neural Sciences, Azienda Ospedaliero-Universitaria, Ospedale Civile di Baggiovara, 41125 Modena, Italy.
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, 37126 Verona, Italy.
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Liyanagedera S, Williams RP, Veraldi S, Nobili V, Mann JP. The pharmacological management of NAFLD in children and adolescents. Expert Rev Clin Pharmacol 2017; 10:1225-1237. [PMID: 28803504 DOI: 10.1080/17512433.2017.1365599] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) represents a spectrum, including 'simple' steatosis, non-alcoholic steatohepatitis (NASH), and fibrosis. Increasing prevalence of NAFLD has followed the international rise in obesity and lifestyle modification is the mainstay therapy for children. To date, pharmacological trials have had varying efficacy but a large number of new agents are in early phase trials for adults. Areas covered: This review explores the effect of current and potential future paediatric NAFLD treatments in terms of histological and biochemical endpoints. The potential for the extension of adult treatments to children is discussed, as well as what limits the use of certain agents in children. Expert commentary: No drugs have yet to be licenced for NAFLD. Trial heterogeneity makes comparison of drugs between studies challenging. FXR agonists are yet to be trialled in children but may represent a safe and potentially efficacious therapy. Future treatments would likely encompass a multimodal approach that may include bariatric surgery.
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Affiliation(s)
- Savinda Liyanagedera
- a Department of Paediatrics , Cardiff University School of Medicine , Cardiff , UK
| | | | - Silvio Veraldi
- b Hepatometabolic Unit , Bambino Gesu Hospital - IRCCS , Rome , Italy.,c Liver Research Unit , Bambino Gesu Hospital, IRCCS , Rome , Italy
| | - Valerio Nobili
- b Hepatometabolic Unit , Bambino Gesu Hospital - IRCCS , Rome , Italy.,c Liver Research Unit , Bambino Gesu Hospital, IRCCS , Rome , Italy
| | - Jake P Mann
- d Metabolic Research Laboratories, Institute of Metabolic Science , University of Cambridge , Cambridge , UK.,e Department of Paediatrics , University of Cambridge , Cambridge , UK
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Yang YJ, Bang CS, Shin SP, Baik GH. Clinical impact of non-alcoholic fatty liver disease on the occurrence of colorectal neoplasm: Propensity score matching analysis. PLoS One 2017; 12:e0182014. [PMID: 28777831 PMCID: PMC5544218 DOI: 10.1371/journal.pone.0182014] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2017] [Accepted: 07/11/2017] [Indexed: 02/07/2023] Open
Abstract
The effect of non-alcoholic fatty liver disease (NAFLD) on the occurrences of colorectal neoplasm (CRN) at surveillance colonoscopy is rarely evaluated. We retrospectively reviewed medical records of 1,023 patients who had both index and surveillance colonoscopy at a single institution. The cumulative occurrence rates of overall and advanced CRN at the time of surveillance colonoscopy were compared between patients with and without NAFLD using propensity score matching analysis. In an analysis of matched cohort of 441 patients, the cumulative rates of overall CRN occurrence at 3 and 5 years after index colonoscopy were higher in subjects with NAFLD than in those without NAFLD (9.1% vs. 5.0% & 35.2% vs. 25.3%, P = 0.01). Cox regression analysis showed that NAFLD independently increased the risk of overall CRN occurrence with marginal significance (adjusted hazard ratio [aHR]: 1.31 95% CI: 1.01-1.71, P = 0.05). Additionally, NAFLD was associated with the development of 3 or more adenomas at the time of surveillance colonoscopy (aHR: 2.49, 95% CI: 1.20-5.20, P = 0.02). In subgroup analysis based on index colonoscopy risk categories, the effect of NAFLD on the overall CRN occurrence at the time of surveillance colonoscopy was confined to the normal group (aHR: 1.47, 95% CI: 1.05-2.06, P = 0.02). Regarding advanced CRN occurrences at the time of surveillance colonoscopy, age was the only significant risk factor (aHR: 1.06, 95% CI: 1.02-1.10, P = 0.001). NAFLD was associated with overall CRN occurrence, especially in patients with no adenoma at the index colonoscopy. NAFLD may be considered for the determination of the time-interval for surveillance colonoscopy, especially the patients with negative index colonoscopy findings.
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Affiliation(s)
- Young Joo Yang
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
| | - Chang Seok Bang
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
- Institue of New Frontier Research, Hallym University College of Medicine, Chuncheon, Korea
| | - Suk Pyo Shin
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
| | - Gwang Ho Baik
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
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Abstract
A growing epidemic of nonalcoholic fatty liver disease (NAFLD) is paralleling the increase in the incidence of obesity and diabetes mellitus in countries that consume a Western diet. As NAFLD can lead to life-threatening conditions such as cirrhosis and hepatocellular carcinoma, an understanding of the factors that trigger its development and pathological progression is needed. Although by definition this disease is not associated with alcohol consumption, exposure to environmental agents that have been linked to other diseases might have a role in the development of NAFLD. Here, we focus on one class of these agents, endocrine-disrupting chemicals (EDCs), and their potential to influence the initiation and progression of a cascade of pathological conditions associated with hepatic steatosis (fatty liver). Experimental studies have revealed several potential mechanisms by which EDC exposure might contribute to disease pathogenesis, including the modulation of nuclear hormone receptor function and the alteration of the epigenome. However, many questions remain to be addressed about the causal link between acute and chronic EDC exposure and the development of NAFLD in humans. Future studies that address these questions hold promise not only for understanding the linkage between EDC exposure and liver disease but also for elucidating the molecular mechanisms that underpin NAFLD, which in turn could facilitate the development of new prevention and treatment opportunities.
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Affiliation(s)
- Charles E Foulds
- Department of Molecular and Cellular Biology, Baylor College of Medicine
- Center for Precision Environmental Health, Baylor College of Medicine
| | - Lindsey S Treviño
- Department of Molecular and Cellular Biology, Baylor College of Medicine
- Center for Precision Environmental Health, Baylor College of Medicine
| | - Brian York
- Department of Molecular and Cellular Biology, Baylor College of Medicine
- Dan L. Duncan Cancer Center, Baylor College of Medicine
| | - Cheryl L Walker
- Department of Molecular and Cellular Biology, Baylor College of Medicine
- Center for Precision Environmental Health, Baylor College of Medicine
- Dan L. Duncan Cancer Center, Baylor College of Medicine
- Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, USA
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Takahashi Y. The Role of Growth Hormone and Insulin-Like Growth Factor-I in the Liver. Int J Mol Sci 2017; 18:ijms18071447. [PMID: 28678199 PMCID: PMC5535938 DOI: 10.3390/ijms18071447] [Citation(s) in RCA: 136] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 06/29/2017] [Accepted: 06/30/2017] [Indexed: 12/17/2022] Open
Abstract
Adult growth hormone deficiency (GHD) is characterized by metabolic abnormalities associated with visceral obesity, impaired quality of life, and increased mortality. Patients with adult GHD show increased prevalence of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), and growth hormone (GH) replacement therapy has been shown to improve these conditions. It has also been demonstrated that a decrease in the GH insulin-like growth factor-I (IGF-I) axis is closely associated with the progression of general NAFLD, suggesting a physiological role of these hormones for the maintenance of the liver. NASH histologically demonstrates inflammation, necrosis, and fibrosis, in addition to steatosis (and is a serious disease because it can progress to liver cirrhosis and hepatocellular carcinoma in a subset of cases). While fibrosis determines the prognosis of the patient, efficacious treatment for fibrosis is crucial; however, it has not yet been established. Recent studies have clarified the essential roles of GH and IGF-I in the liver. GH profoundly reduces visceral fat, which plays an important role in the development of NAFLD. Furthermore, GH directly reduces lipogenesis in the hepatocytes. IGF-I induces cellular senescence and inactivates hepatic stellate cells, therefore ameliorating fibrosis. IGF-I treatment has been shown to improve animal models of NASH and cirrhosis, suggesting potential clinical applications of IGF-I in these conditions. In this review, I will focus on the important roles of GH and IGF-I in the liver, their underlying mechanisms, and their potential therapeutic applications.
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Affiliation(s)
- Yutaka Takahashi
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
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