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Cetti F, Ossoli A, Garavaglia C, Da Dalt L, Norata GD, Gomaraschi M. PPAR-mediated reduction of lipid accumulation in hepatocytes involves the autophagy-lysosome-mitochondrion axis. Ann Med 2025; 57:2497112. [PMID: 40289698 PMCID: PMC12039397 DOI: 10.1080/07853890.2025.2497112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 03/25/2025] [Accepted: 04/15/2025] [Indexed: 04/30/2025] Open
Abstract
BACKGROUND AND AIM Lipid accumulation in hepatocytes is reduced by the activation of the peroxisome proliferator-activated receptor (PPAR) α, which is associated with increased lysosomal acid lipase (LAL) activity, transcription factor EB (TFEB) expression, and mitochondrial β-oxidation.Aim of the study was to assess whether the three isoforms of PPAR, i.e. α, δ and γ, share the same ability to reduce lipid accumulation in hepatocytes and to clarify the involvement of autophagy activation, lysosomal hydrolysis, and mitochondrial β-oxidation in lipid clearance induced by PPARs. METHODS HepG2 cells were treated with oleate/palmitate (O/P) to induce lipid accumulation and exposed to the PPARα agonist fenofibric acid, the γ agonist pioglitazone, the δ agonist seladelpar, or the dual α/γ agonist saroglitazar. RESULTS The treatment of HepG2 cells with fenofibric acid, pioglitazone, seladelpar, or saroglitazar halved lipid accumulation induced by O/P. PPAR agonists increased TFEB, p62, and LC3 expression and rescued LAL impairment induced by O/P. Moreover, PPAR agonists significantly increased mitochondrial mass and the expression of genes involved in mitochondrial dynamics and fatty acid catabolism. Interestingly, PPAR agonists lost their ability to reduce lipid accumulation when autophagic flux, LAL activity, or fatty acid transport in the mitochondria were blocked by specific inhibitors. CONCLUSION All PPAR agonists were able to promote the clearance of lipids in cells loaded with long-chain fatty acids. The key role of acid hydrolysis to generate fatty acids, which can be then catabolized in the mitochondria, and the ability of the PPAR system to sustain each phase of this clearing process were elucidated.
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Affiliation(s)
- Federica Cetti
- Center E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Alice Ossoli
- Center E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Carola Garavaglia
- Center E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Lorenzo Da Dalt
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Giuseppe Danilo Norata
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Monica Gomaraschi
- Center E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
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Machado-Silva L, Terra C, Campos CF, Lanzoni V, Miguez M, Perazzo H, Gomes MB, Perez RM. The use of simple tests to predict biopsy-proven steatohepatitis in people with type 2 diabetes. Eur J Gastroenterol Hepatol 2025; 37:320-326. [PMID: 39919007 DOI: 10.1097/meg.0000000000002890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/09/2025]
Abstract
BACKGROUND/AIMS Metabolic-associated steatotic liver disease (MASLD) has become the most common chronic liver disease, especially in people with type 2 diabetes mellitus (T2DM). Liver biopsy remains the gold standard method for diagnosis of MASLD subtypes, but prevalences may be under or overestimated when biopsy is performed with selection bias. The aims of this study were to define prevalence of MASLD subtypes by liver biopsy in T2DM participants not selected by abnormal exams, determine variables associated with metabolic-associated steatohepatitis (MASH), and analyze performance of aminotransferases and abdominal ultrasound in diagnosis. METHODS T2DM participants from 18 to 70 years were considered for enrollment. Of the 396 participants, 85 were included and submitted to clinical, laboratory examinations, and ultrasound. Eighty-three performed liver biopsy evaluated by two independent pathologists. Factors independently associated to MASH and significant fibrosis were assessed by hierarchical multivariate logistic regression. RESULTS Prevalence of MASLD was 92% (50% simple steatosis, 42% MASH) and kappa = 0.78. Steatosis was mild in 76% of participants with simple steatosis and severe in 65% of MASH (P < 0.001). Presence of MASH or fibrosis was associated with BMI and alanine aminotransferase (ALT) [threshold of 33.5 mg/dl in predicting MASH (area under the curve = 0.82, P = 0.001)]. CONCLUSION Prevalence of MASLD by liver biopsy in T2DM regardless of ultrasound or ALT elevation is almost 100%, with 42% of MASH. MASH was associated to severe steatosis on histology. BMI and ALT were independently associated with MASH and ALT close to the upper limit of normal gave the best cutoff point for MASH detection.
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Affiliation(s)
- Lilian Machado-Silva
- Medical Division, Gastroenterology Unit, Air Force Central Hospital (HCA), Brazilian Air Force (FAB)
| | - Carlos Terra
- Department of Internal Medicine, Liver Unit, Pedro Ernesto University Hospital, State University of Rio de Janeiro
- Department of Internal Medicine, Liver Unit, Lagoa Federal Hospital
| | | | - Valeria Lanzoni
- Department of Pathology, Federal University of São Paulo, São Paulo
| | - Marcio Miguez
- Department of Internal Medicine, Radiology Unit, Pedro Ernesto University Hospital, State University of Rio de Janeiro
| | - Hugo Perazzo
- Laboratory of STI and HIV, Evandro Chagas National Institute of Infectious Diseases (INI), Oswaldo Cruz Foundation (FIOCRUZ)
| | - Marilia Brito Gomes
- Department of Internal Medicine, Diabetes Unit, Pedro Ernesto University Hospital, State University of Rio de Janeiro
| | - Renata M Perez
- Department of Internal Medicine, School of Medicine, Federal University of Rio de Janeiro (UFRJ)
- D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil
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Sharma D, Patel D, Mandal P. In Vitro, In Vivo, and In Silico Investigation of Synbiotic-Mediated Activation of PPAR- α Curtails Nonalcoholic Steatohepatitis (NASH) in Wistar Rats by Inhibiting PNPLA3/SREBP1-c Lead Inflammatory Injury of Hepatic Cells. Mediators Inflamm 2025; 2025:9948679. [PMID: 40017524 PMCID: PMC11865469 DOI: 10.1155/mi/9948679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 07/31/2024] [Accepted: 01/21/2025] [Indexed: 03/01/2025] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is an inflammation of the liver and a menace to human health. To treat NASH various pharmaceutical products have been used, but their prohibitive side effects limit their effectiveness. NASH, a multihit hypothesis involves high-fat diet and signals from the gut to the liver. Lactobacillus plantarum (probiotic) and aged garlic extract (AGE, a prebiotic) are antioxidative and anti-inflammatory and may be a latent combination therapy for NASH. The NASH model was developed using Wistar rats and treatments were administered to understand the mechanism. Initially, in the in vitro models, transepithelial electrical resistance (TEER) 2'-7'-dichlorodihydrofluorescein diacetate (DCFDA), 4-6-diamidino-2-phenylindole (DAPI) labeling and Oil Red O (ORO) conducted on HepG2 and Caco2 cells. Afterwards, in in vivo studies rat liver tissues were examined through confocal microscopy using the ORO staining and hematoxylin and eosin (H/E) stain, malondialdehyde (MDA), and biochemical indices were recorded. The levels of patatin-like phospholipase domain-containing protein 3 (PNPLA3) and sterol regulatory element binding protein-1c (SREBP-1c), peroxisome proliferators activated receptors (PPARs)-α, inflammatory, and apoptotic biomarkers were quantified by qRT-PCR. Synbiotic reduced the hepatic inflammation and apoptosis examined through the levels of PNPLA3, SREBP-1c, IL-6, TGF-β, Bcl-2, and caspase-3 in NASH models. In turn, the gram-negative species and bacterial translocation associated were reduced. Consequently, the Insilco analysis supports the theory that each (eight) bioactive compound of AGE targets PNPLA3 and enhances the PPAR-α activity. Additionally, PPAR-α inhibitors upregulated the PNPLA3 and SREBP-1C expression. As a result, the synbiotic may inhibit NASH progression by affecting PNPLA3/SREBP1-c through PPAR-α.
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Affiliation(s)
- Dixa Sharma
- Department of Biology, P. D. Patel Institute of Applied Sciences, Charotar University of Science and Technology, Changa, Anand 3888421, Gujarat, India
| | - Dhara Patel
- Department of Biology, P. D. Patel Institute of Applied Sciences, Charotar University of Science and Technology, Changa, Anand 3888421, Gujarat, India
| | - Palash Mandal
- Department of Biology, P. D. Patel Institute of Applied Sciences, Charotar University of Science and Technology, Changa, Anand 3888421, Gujarat, India
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He X, Zhang S, Bai Q, Pan M, Jiang Y, Liu W, Li W, Gong Y, Li X. Air pollution exposure and prevalence of non-alcoholic fatty liver disease and related cirrhosis: A systematic review and meta-analysis. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 289:117469. [PMID: 39657383 DOI: 10.1016/j.ecoenv.2024.117469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 11/26/2024] [Accepted: 12/02/2024] [Indexed: 12/12/2024]
Abstract
BACKGROUND AND OBJECTIVE A systematic review and meta-analysis were used to investigate the relationship between air pollution exposure and the prevalence of non-alcoholic fatty liver disease (NAFLD) and its related cirrhosis. Through this study, we hope to clarify the potential public health risks of air pollution as an environmental exposure factor. METHODS Through a comprehensive and systematic search of the EMBASE, PubMed, Web of Science, and Cochrane library databases, studies published up to March 30, 2024, that met the eligibility criteria were identified. The meta-analysis aimed to determine the association between air pollution exposure and NAFLD risk. Subgroup analyses were conducted based on regional economic development after adjusting for confounding factors. The combined odds ratio (OR) was calculated, publication bias was assessed using funnel plots, and consideration was given to heterogeneity among study-specific relative risks. RESULTS This review included 14 observational studies (including 7 cohort studies and 7 cross-sectional studies) involving 43,475,41 participants. The pooled analysis showed that PM2.5, NOx, PM10, PM2.5-10, passive smoking, PM1, and air pollution from solid fuels were positively associated with the incidence and prevalence of NAFLD and its related cirrhosis. The risk ratios for PM2.5, NOx, PM10, PM2.5-10, passive smoking, and air pollution from solid fuels for NAFLD and its related cirrhosis were 1.33 (95 % CI: 1.25, 1.42), 1.19 (95 % CI: 1.14, 1.23), 1.27 (95 % CI: 1.05, 1.55), 1.05 (95 % CI: 1.00, 1.11), 1.53 (95 % CI: 1.12, 2.09), 1.50 (95 % CI: 0.86, 2.63), and 1.18 (95 % CI: 0.85, 1.63), respectively. In contrast, the risk ratio for O3 was 0.75 (95 % CI: 0.69, 0.83), suggesting that O3 may lower the incidence and prevalence of NAFLD and its related cirrhosis. We also conducted subgroup analyses based on the level of national development to examine the impact of PM2.5 on NAFLD and its related cirrhosis. The results showed that the risk of NAFLD and its related cirrhosis associated with PM2.5 in developing countries was 1.41 (95 % CI: 1.29, 1.53), which was higher than 1.20 (95 % CI: 1.12, 1.29) in developed countries. CONCLUSION The study findings show that PM2.5, NOx, PM10, PM2.5-10, passive smoking, PM1, and air pollution from solid fuels can increase an individual's risk of developing NAFLD and its related cirrhosis; while O3 can reduce the risk. In developing countries, the risk level of NAFLD and its related cirrhosis due to PM2.5 is higher than that in developed countries.
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Affiliation(s)
- Xingyi He
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, PR China
| | - Shipeng Zhang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, PR China
| | - Qinglin Bai
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, PR China
| | - Moshen Pan
- School of Economics, Shanghai University of Finance and Economics, Shanghai 200433, PR China
| | - Yanjie Jiang
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, No.157 Daming Road, Nanjing 210022, PR China
| | - Weiwei Liu
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
| | - Wei Li
- Department of Intensive Care Medicine, Sichuan Hospital of Integrated Traditional Chinese and Western Medicine, Chengdu 610041, PR China
| | - Yuanyuan Gong
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China.
| | - Xueping Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China.
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Mirzaei F, Abbasi E, Mirzaei A, Hosseini NF, Naseri N, Khodadadi I, Jalili C, Majdoub N. Toxicity and Hepatoprotective Effects of ZnO Nanoparticles on Normal and High-Fat Diet-Fed Rat Livers: Mechanism of Action. Biol Trace Elem Res 2025; 203:199-217. [PMID: 38441796 DOI: 10.1007/s12011-024-04108-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 02/13/2024] [Indexed: 10/11/2024]
Abstract
This experiment aimed to evaluate the beneficial and toxic properties of synthetic zinc oxide nanoparticles (ZnO NPs) on the liver of normal and high-fat diet (HFD) fed-rats. The ZnO NPs were synthesized and, its characterizations were determined by different techniques. Effect of ZnO NP on cell viability, liver enzymes and lipid accumulation were measured in HepG2 cells after 24 h. After that, rats orally received various dosages of ZnO NPs for period of 4 weeks. Toxicity tests were done to determine the appropriate dose. In the subsequent step, the hepatoprotective effects of 5 mg/kg ZnO NPs were determined in HFD-fed rats (experiment 2). The oxidative stress, NLRP3 inflammasome, inflammatory, and apoptosis pathways were measured. Additionally, the activity of caspase 3, nitric oxide levels, antioxidant capacity, and various biochemical factors were measured. Morphological changes in the rat livers were also evaluated by hematoxylin and eosin (H & E) and Masson trichrome. Liver apoptosis rate was also approved by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Treatment of animals with 5 mg/ZnO NPs revealed potential hepatoprotective properties, while ZnO NPs at the doses of above 10 mg/kg showed toxic effects. Antioxidant enzyme gene expression and activity were significantly augmented, while apoptosis, NLRP3 inflammasome, and inflammation pathways were significantly reduced by 5 mg/kg ZnO NPs. Liver histopathological alterations were restored by 5 mg/kg ZnO NPs in HFD. Our study highlights the hepatoprotective effects of ZnO NPs against the HFD-induced liver damage, involving antioxidant, anti-inflammatory, and anti-apoptotic pathways, indicating their promising therapeutic potential.
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Affiliation(s)
- Fatemeh Mirzaei
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ebrahim Abbasi
- Department of Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Amir Mirzaei
- Centre Énergie, Matériaux Et Télécommunications, Institut National de La Recherche Scientifique, 1650 Boulevard Lionel-Boulet, Varennes, Québec, J3X 1P7, Canada
| | - Nashmin Fayazi Hosseini
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Nima Naseri
- Department of Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Iraj Khodadadi
- Department of Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Cyrus Jalili
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Nesrine Majdoub
- Faculdade de Ciências E Tecnologia, Universidade Do Algarve, Campus de Gambelas, 8005-139, Faro, MeditBio, Portugal
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Ciardullo S, Morabito G, Rea F, Savaré L, Perseghin G, Corrao G. Time Trends in Liver-Related Mortality in People With and Without Diabetes: Results From a Population-Based Study. J Clin Endocrinol Metab 2024; 109:2513-2519. [PMID: 38506158 PMCID: PMC11403322 DOI: 10.1210/clinem/dgae182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 02/28/2024] [Accepted: 03/18/2024] [Indexed: 03/21/2024]
Abstract
CONTEXT Patients with diabetes are at increased risk of dying from liver-related events, but little is known on whether this increased risk has changed in recent years. OBJECTIVE The aim of the present study is to describe time trends in cause-specific liver-related mortality in people with and without diabetes from the general Italian population. METHODS Data were retrieved from the health care utilization databases of Lombardy, a region of Italy that accounts for about 16% (almost 10 million) of its population. Annual cause-specific mortality rates and proportionate mortality were computed among individuals with and without diabetes from 2010 to 2019. Liver-related deaths were categorized as viral, alcohol related, and nonviral nonalcohol related (NVNA). RESULTS Liver diseases were responsible for 2% and 1% of deaths in people with and without diabetes (2019). Among patients with diabetes, the crude mortality rate for liver diseases decreased from 1.13 to 0.64 deaths per 1000 person-years from 2010 to 2019. The largest proportion of liver-related deaths was attributable to NVNA diseases and it increased from 63% in 2010 to 68% in 2019, with a corresponding relative reduction of viral causes (from 27% to 23%). The standardized mortality ratio for patients with diabetes was 3.35 (95% CI 2.96-3.76) for NVNA, 1.66 (95% CI 1.33-2.01) for viral hepatitis, and 1.61 (95% CI 1.13-2.17) for alcoholic liver disease and it remained relatively stable over time. Excess mortality risk in patients with diabetes for liver-related mortality was higher than for cardiovascular mortality and cancer. CONCLUSION While liver-related mortality rates decreased significantly among patients with diabetes, NVNA causes made up the majority of cases. Excess mortality for liver-related causes in patients with diabetes compared with controls remained constant in the studied period.
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Affiliation(s)
- Stefano Ciardullo
- Department of Medicine and Rehabilitation, Policlinico di Monza, Monza, 20900, Italy
- School of Medicine and Surgery, University of Milano Bicocca, Milan, 20126, Italy
| | - Gabriella Morabito
- National Centre for Healthcare Research & Pharmacoepidemiology, University of Milano-Bicocca, Milan, 20126, Italy
- Laboratory of Healthcare Research & Pharmacoepidemiology, Unit of Biostatistics, Epidemiology and Public Health, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, 20126, Italy
| | - Federico Rea
- National Centre for Healthcare Research & Pharmacoepidemiology, University of Milano-Bicocca, Milan, 20126, Italy
- Laboratory of Healthcare Research & Pharmacoepidemiology, Unit of Biostatistics, Epidemiology and Public Health, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, 20126, Italy
| | - Laura Savaré
- National Centre for Healthcare Research & Pharmacoepidemiology, University of Milano-Bicocca, Milan, 20126, Italy
- Department of Mathematics, MOX-Laboratory for Modeling and Scientific Computing, Politecnico di Milano, Milan, 20126, Italy
- CHDS-Center for Health Data Science, Human Technopole, Milan, 20126, Italy
| | - Gianluca Perseghin
- Department of Medicine and Rehabilitation, Policlinico di Monza, Monza, 20900, Italy
- School of Medicine and Surgery, University of Milano Bicocca, Milan, 20126, Italy
| | - Giovanni Corrao
- National Centre for Healthcare Research & Pharmacoepidemiology, University of Milano-Bicocca, Milan, 20126, Italy
- Laboratory of Healthcare Research & Pharmacoepidemiology, Unit of Biostatistics, Epidemiology and Public Health, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, 20126, Italy
- Directorate General for Health, Milan, 20126, Italy
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Choudhury A, Singh SP, Desmukh A, Sahoo B, Eslam M. Post-Liver Transplant Metabolic Syndrome. J Clin Exp Hepatol 2024; 14:101368. [PMID: 38523736 PMCID: PMC10960134 DOI: 10.1016/j.jceh.2024.101368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 02/14/2024] [Indexed: 03/26/2024] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is the second most frequent cause of liver transplantation following alcoholic liver disease. With longer follow-up and increased survival rates, the occurrence rate of the metabolic syndrome is increasing with time among liver transplant recipients. Reappearances of non-alcoholic fatty liver disease after transplantation, both as recurring cases and new instances, are prevalent; nonetheless, the recurrence of fibrosis is minimal. Recognizing populations at elevated risk and enhancing the management of metabolic-related conditions are crucial for maintaining a healthy transplanted organ, particularly considering the prolonged utilization of immunosuppressive treatments. Furthermore, NASH-related cirrhosis patients who had transplant are at a greater risk of cardiovascular, renal events and increased incidence of cancer, necessitating a unique care strategy. This review discusses post-transplant metabolic syndrome, risk factors, pathogenesis, diagnosis, prevention strategy, recurrent and de novo NAFLD and customized immunosuppression.
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Affiliation(s)
- Ashok Choudhury
- Dept of Hepatology and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Satender P. Singh
- Dept of Hepatology and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Akhil Desmukh
- Dept of Hepatology and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Bishnupriya Sahoo
- Associate Professor of Pediatrics, Consultant Pediatric Gastroenterology, Hepatology and Liver Transplant, SGT University, Gurugram, Haryana, India
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia
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Zhu Y, Yuan Y, Si H, Li S, Zhao F, Mu R, Lin Z, Wang X, Qiu Q, Xu C, Ji L, Li Z. Lipidomic and transcriptomic profiles provide new insights into the triacylglycerol and glucose handling capacities of the Arctic fox. Front Vet Sci 2024; 11:1388532. [PMID: 38988981 PMCID: PMC11233799 DOI: 10.3389/fvets.2024.1388532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 06/10/2024] [Indexed: 07/12/2024] Open
Abstract
The Arctic fox (Vulpes lagopus) is a species indigenous to the Arctic and has developed unique lipid metabolism, but the mechanisms remain unclear. Here, the significantly increased body weight of Arctic foxes was consistent with the significantly increased serum very-low-density lipoprotein (VLDL), and the 40% crude fat diet further increased the Arctic fox body weight. The enhanced body weight gain stems primarily from increased subcutaneous adipose tissue accumulation. The adipose triacylglycerol and phosphatidylethanolamine were significantly greater in Arctic foxes. The adipose fatty-acid synthase content was significantly lower in Arctic foxes, highlighting the main role of exogenous fatty-acids in fat accumulation. Considering the same diet, liver-derived fat dominates adipose expansion in Arctic foxes. Liver transcriptome analysis revealed greater fat and VLDL synthesis in Arctic foxes, consistent with the greater VLDL. Glucose homeostasis wasn't impacted in Arctic foxes. And the free fatty-acids in adipose, which promote insulin resistance, also did not differ between groups. However, the hepatic glycogen was greater in Arctic foxes and transcriptome analysis revealed upregulated glycogen synthesis, improving glucose homeostasis. These results suggest that the superior fat accumulation capacity and distinct characteristics of hepatic and adipose lipid and glucose metabolism facilitate glucose homeostasis and massive fat accumulation in Arctic foxes.
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Affiliation(s)
- Yuhang Zhu
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Yuan Yuan
- School of Ecology and Environment, Northwestern Polytechnical University, Xi’an, China
| | - Huazhe Si
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
- Key Lab of Animal Production, Product Quality and Security, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Songze Li
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Fei Zhao
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Ruina Mu
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Zihan Lin
- College of Plant Protection, Jilin Agricultural University, Changchun, China
| | - Xiaoxu Wang
- Department of Special Animal Nutrition and Feed Science, Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Qiang Qiu
- School of Ecology and Environment, Northwestern Polytechnical University, Xi’an, China
| | - Chao Xu
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Lele Ji
- National Demonstration Center for Experimental Preclinical Medicine Education, The Fourth Military Medical University, Xi'an, China
| | - Zhipeng Li
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
- Key Lab of Animal Production, Product Quality and Security, Ministry of Education, Jilin Agricultural University, Changchun, China
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Thakur S, Kumar V, Das R, Sharma V, Mehta DK. Biomarkers of Hepatic Toxicity: An Overview. CURRENT THERAPEUTIC RESEARCH 2024; 100:100737. [PMID: 38860148 PMCID: PMC11163176 DOI: 10.1016/j.curtheres.2024.100737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 01/31/2024] [Indexed: 06/12/2024]
Abstract
Background Hepatotoxicity is the foremost issue for clinicians and the primary reason for pharmaceutical product recalls. A biomarker is a measurable and quantifiable attribute used to evaluate the efficacy of a treatment or to diagnose a disease. There are various biomarkers which are used for the detection of liver disease and the intent of liver damage. Objective This review aims to investigate the current state of hepatotoxicity biomarkers and their utility in clinical settings. Using hepatic biomarkers, the presence of liver injury, its severity, prognosis, causative agent, and type of hepatotoxicity can all be determined. Methods Relevant published articles up to 2022 were systematically retrieved from MEDLINE/PubMed, SCOPUS, EMBASE, and WOS databases using keywords such as drug toxicity, hepatotoxicity biomarkers, biochemical parameters, and nonalcoholic fatty liver disease. Results In clinical trials and everyday practice, biomarkers of drug-induced liver injury are essential for spotting the most severe cases of hepatotoxicity. Hence, developing novel biomarker approaches to enhance hepatotoxicity diagnosis will increase specificity and/or identify the person at risk. Importantly, early clinical studies on patients with liver illness have proved that some biomarkers such as aminotransferase, bilirubin, albumin, and bile acids are even therapeutically beneficial. Conclusions By assessing the unique signs of liver injury, health care professionals can rapidly and accurately detect liver damage and evaluate its severity. These measures contribute to ensuring prompt and effective medical intervention, hence reducing the risk of long-term liver damage and other major health concerns.
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Affiliation(s)
- Simran Thakur
- Department of Pharmacy Practice, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
| | - Vishal Kumar
- Department of Pharmacy Practice, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
| | - Rina Das
- Department of Pharmaceutical Chemistry, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
| | - Vishal Sharma
- Department of Pharmaceutical Chemistry, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
| | - Dinesh Kumar Mehta
- Department of Pharmaceutical Chemistry, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
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Motamed N, Zamani F, Maadi M, Ajdarkosh H, Roozafzai F, Keyvani H, Poustchi H, Shakeri R, Ashrafi GH, Perumal D, Rabiee B, Moradi-Lakeh M, Khoonsari M, Kheyri Z, Sohrabi MR, Doustmohammadian A, Amirkalali B, Safarnezhad Tameshkel F, Gholizadeh E, Hosseini SH, Karbalaie Niya MH. A population-based prospective study on obesity-related non-communicable diseases in northern Iran: rationale, study design, and baseline analysis. Front Endocrinol (Lausanne) 2024; 15:1329380. [PMID: 38681770 PMCID: PMC11046460 DOI: 10.3389/fendo.2024.1329380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Accepted: 03/11/2024] [Indexed: 05/01/2024] Open
Abstract
Background Iran is facing an epidemiological transition with the increasing burden of non-communicable diseases, such as obesity-related disorders and cardiovascular diseases (CVDs). We conducted a population-based prospective study to assess the prevalence and incidence rates of CVDs and obesity-related metabolic disorders and to evaluate the predictive ability of various CVD risk assessment tools in an Iranian population. Method We enrolled 5,799 participants in Amol, a city in northern Iran, in 2009-2010 and carried out the first repeated measurement (RM) after seven years (2016-2017). For all participants, demographic, anthropometric, laboratory, hepatobiliary imaging, and electrocardiography data have been collected in the enrollment and the RM. After enrollment, all participants have been and will be followed up annually for 20 years, both actively and passively. Results We adopted a multidisciplinary approach to overcome barriers to participation and achieved a 7-year follow-up success rate of 93.0% with an active follow-up of 5,394 participants aged 18-90 years. In the RM, about 64.0% of men and 81.2% of women were obese or overweight. In 2017, about 16.2% and 5.2% of men had moderate or severe non-alcoholic fatty liver disease, while women had a significantly higher prevalence of metabolic syndrome (35.9%), and type 2 diabetes mellitus (20.9%) than men. Of 160 deceased participants, 69 cases (43.1%) died due to CVDs over seven years. Conclusion The most prevalent obesity-related chronic disease in the study was metabolic syndrome. Across the enrollment and RM phases, women exhibited a higher prevalence of obesity-related metabolic disorders. Focusing on obesity-related metabolic disorders in a population not represented previously and a multidisciplinary approach for enrolling and following up were the strengths of this study. The study outcomes offer an evidence base for future research and inform policies regarding non-communicable diseases in northern Iran.
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Affiliation(s)
- Nima Motamed
- Department of Social Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Farhad Zamani
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mansooreh Maadi
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Ajdarkosh
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Farzin Roozafzai
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Keyvani
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Poustchi
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ramin Shakeri
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Dhayaneethie Perumal
- Faculty of Science, Engineering and Computing, Kingston University, London, United Kingdom
| | - Behnam Rabiee
- Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Maziar Moradi-Lakeh
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
- Preventive Medicine and Public Health Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mahmoodreza Khoonsari
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Zahedin Kheyri
- Department of Internal Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Masoud Reza Sohrabi
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Azam Doustmohammadian
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Bahareh Amirkalali
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Esmaeel Gholizadeh
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Hamzeh Hosseini
- Psychiatry and Behavioral Sciences Research Center, Addiction Institute, Mazandaran University of Medical Sciences, Sari, Iran
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11
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Elsaid MI, Bridges JFP, Mumtaz K, Li N, Sobotka L, Rustgi VK, Paskett ED. The impact of metabolic syndrome severity on racial and ethnic disparities in Metabolic Dysfunction-Associated Steatotic Liver Disease. PLoS One 2024; 19:e0299836. [PMID: 38489287 PMCID: PMC10942082 DOI: 10.1371/journal.pone.0299836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 02/15/2024] [Indexed: 03/17/2024] Open
Abstract
BACKGROUND & AIMS Previous studies have examined the effects of metabolic syndrome (MetS) rather than its severity on race and ethnic disparities in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). We used the MetS severity score, a validated sex-race-ethnicity-specific severity measure, to examine the effects of race/ethnicity on the association between MetS severity and MASLD. METHODS This study included 10,605 adult participants from the Third National Health and Nutrition Examination Survey. The MASLD diagnosis was based on ultrasound findings in patients without excessive alcohol intake or other liver diseases. MetS severity Z-scores were calculated and stratified into four categories low (1st-50th), moderate (>50th-75th), high (>75th-90th), and very high (>90th+)]. Multivariable adjusted logistic regression models with complex survey methods were used to test the effect of MetS severity on MASLD. RESULTS The age-adjusted MASLD prevalence was 17.4%, 25.7%, 42.5, and 54.9% in adults with mild, moderate, high, and very high MetS severities, respectively (P-trend <0.001). MetS severity was significantly higher in patients with MASLD than in those without [mean percentile 60th vs. 44th, P<0.001]. Among patients with MASLD, Mexican-American and Black non-Hispanic females had significantly higher age-adjusted MetS severity (68th and 61st, respectively) than White non-Hispanic females 54th, while Black non-Hispanic males had significantly lower MetS severity (56th) than White non-Hispanic males (70th) (P-Interaction = 0.02). Adults with high and very high MetS severity had 2.27 (95% CI:1.70 to 3.03) and 3.12 (95% CI:2.20 to 4.42), respectively, higher adjusted odds of MASLD than those with mild MetS severity. CONCLUSIONS Racial/ethnic disparities in MetS severity play a pivotal role in the risk of MASLD. Our findings highlight the potential clinical utility of the MetS severity score in identifying at-risk individuals, which will help guide targeted prevention and tailoring management strategies to mitigate the MASLD burden.
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Affiliation(s)
- Mohamed I. Elsaid
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America
- Center for Biostatistics, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America
- Department of Internal Medicine, Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - John F. P. Bridges
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America
- Department of Health, Behavior and Society, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
| | - Khalid Mumtaz
- Division of Gastroenterology, Hepatology, & Nutrition, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Na Li
- Division of Gastroenterology, Hepatology, & Nutrition, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Lindsay Sobotka
- Division of Gastroenterology, Hepatology, & Nutrition, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Vinod K. Rustgi
- Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America
- Center for Liver Diseases and Masses, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America
| | - Electra D. Paskett
- Division of Population Sciences, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
- Department of Internal Medicine, Division of Cancer Prevention and Control, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America
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12
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Li YJ, Baumert BO, Stratakis N, Goodrich JA, Wu HT, He JX, Zhao YQ, Aung MT, Wang HX, Eckel SP, Walker DI, Valvi D, La Merrill MA, Ryder JR, Inge TH, Jenkins T, Sisley S, Kohli R, Xanthakos SA, Baccarelli AA, McConnell R, Conti DV, Chatzi L. Circulating microRNA expression and nonalcoholic fatty liver disease in adolescents with severe obesity. World J Gastroenterol 2024; 30:332-345. [PMID: 38313232 PMCID: PMC10835537 DOI: 10.3748/wjg.v30.i4.332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 12/04/2023] [Accepted: 01/09/2024] [Indexed: 01/26/2024] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in children and adolescents. NAFLD ranges in severity from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH), wherein hepatocellular inflammation and/or fibrosis coexist with steatosis. Circulating microRNA (miRNA) levels have been suggested to be altered in NAFLD, but the extent to which miRNA are related to NAFLD features remains unknown. This analysis tested the hypothesis that plasma miRNAs are significantly associated with histological features of NAFLD in adolescents. AIM To investigate the relationship between plasma miRNA expression and NAFLD features among adolescents with NAFLD. METHODS This study included 81 adolescents diagnosed with NAFLD and 54 adolescents without NAFLD from the Teen-Longitudinal Assessment of Bariatric Surgery study. Intra-operative core liver biopsies were collected from participants and used to characterize histological features of NAFLD. Plasma samples were collected during surgery for miRNA profiling. A total of 843 plasma miRNAs were profiled using the HTG EdgeSeq platform. We examined associations of plasma miRNAs and NAFLD features using logistic regression after adjusting for age, sex, race, and other key covariates. Ingenuity Pathways Analysis was used to identify biological functions of miRNAs that were associated with multiple histological features of NAFLD. RESULTS We identified 16 upregulated plasma miRNAs, including miR-193a-5p and miR-193b-5p, and 22 downregulated plasma miRNAs, including miR-1282 and miR-6734-5p, in adolescents with NAFLD. Moreover, 52, 16, 15, and 9 plasma miRNAs were associated with NASH, fibrosis, ballooning degeneration, and lobular inflammation, respectively. Collectively, 16 miRNAs were associated with two or more histological features of NAFLD. Among those miRNAs, miR-411-5p was downregulated in NASH, ballooning, and fibrosis, while miR-122-5p, miR-1343-5p, miR-193a-5p, miR-193b-5p, and miR-7845-5p were consistently and positively associated with all histological features of NAFLD. Pathway analysis revealed that most common pathways of miRNAs associated with multiple NAFLD features have been associated with tumor progression, while we also identified linkages between miR-122-5p and hepatitis C virus and between miR-199b-5p and chronic hepatitis B. CONCLUSION Plasma miRNAs were associated with NAFLD features in adolescent with severe obesity. Larger studies with more heterogeneous NAFLD phenotypes are needed to evaluate miRNAs as potential biomarkers of NAFLD.
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Affiliation(s)
- Yi-Jie Li
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, United States
| | - Brittney O Baumert
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, United States
| | - Nikos Stratakis
- Barcelona Institute of Global Health, Barcelona Institute of Global Health, Barcelona 08036, Spain
| | - Jesse A Goodrich
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, United States
| | - Hao-Tian Wu
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032, United States
| | - Jing-Xuan He
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, United States
| | - Yin-Qi Zhao
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, United States
| | - Max T Aung
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, United States
| | - Hong-Xu Wang
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, United States
| | - Sandrah P Eckel
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, United States
| | - Douglas I Walker
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30329, United States
| | - Damaskini Valvi
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Michele A La Merrill
- Department of Environmental Toxicology, University of California, Davis, CA 95616, United States
| | - Justin R Ryder
- Department of Surgery, Lurie Children’s Hospital of Chicago, Chicago, IL 60611, United States
- Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Thomas H Inge
- Department of Surgery, Lurie Children’s Hospital of Chicago, Chicago, IL 60611, United States
- Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Todd Jenkins
- Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, United States
| | - Stephanie Sisley
- Department of Pediatrics, Children’s Nutrition Research Center USDA/ARS, Baylor College of Medicine, Houston, TX 77030, United States
| | - Rohit Kohli
- Department of Gastroenterology, Children’s Hospital Los Angeles, Los Angeles, CA 90027, United States
| | - Stavra A Xanthakos
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, United States
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States
| | - Andrea A Baccarelli
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032, United States
| | - Rob McConnell
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, United States
| | - David V Conti
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, United States
| | - Lida Chatzi
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, United States
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13
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Parsi A, Hajiani E, Sadani S, Hashemi SJ, Seyedian SS, Alimadadi M, Ghanbari R. Liver Fibrosis and Cirrhosis in Patients with Non-alcoholic Fatty Liver with and without History of Cholecystectomy: A Pilot Study. Middle East J Dig Dis 2024; 16:34-38. [PMID: 39050095 PMCID: PMC11264833 DOI: 10.34172/mejdd.2024.366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 11/09/2023] [Indexed: 07/27/2024] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in the world. Previous studies revealed that cholecystectomy may be considered a risk factor for the development of NAFLD. The aim of this study was to compare the amount of liver fibrosis, determined by elastography, between patients with NAFLD with and without a history of cholecystectomy. Methods In this descriptive-analytical cross-sectional study, 50 patients with NAFLD were divided into two groups: one with a history of cholecystectomy and the other without. No significant differences were found between these two groups in terms of age or sex distribution. Liver fibrosis was measured for all patients using an elastography imaging system. Subsequently, the data related to liver fibrosis, along with the demographic information of the patients, were statistically analyzed using SPSS software version 22. Results The mean elastography score in all patients was 10.66±12.18 kPa (the elasticity scale ranging from 3.80 to 66.40 kPa). The group with a history of cholecystectomy had a significantly higher mean elastography score (13.39±16.20 kPa) compared with the group without cholecystectomy (7.93±4.99 kPa) (P=0.02). Additionally, there was a significant positive correlation between body mass index (BMI) and the mean elastography score in the group of patients with a history of cholecystectomy. Conclusion The mean elastography score of patients with NAFLD with a history of cholecystectomy was approximately twice as high as that of non-cholecystectomy patients.
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Affiliation(s)
- Abazar Parsi
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Eskandar Hajiani
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Somayeh Sadani
- Clinical Research Development Unit (CRDU), Sayad Shirazi Hospital, Golestan University of Medical Sciences, Gorgan, Iran
| | - Seid Jalal Hashemi
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seid Saeed Seyedian
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mehdi Alimadadi
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Reza Ghanbari
- Gene Therapy Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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14
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Ruiz de Porras V, Figols M, Font A, Pardina E. Curcumin as a hepatoprotective agent against chemotherapy-induced liver injury. Life Sci 2023; 332:122119. [PMID: 37741319 DOI: 10.1016/j.lfs.2023.122119] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/20/2023] [Accepted: 09/20/2023] [Indexed: 09/25/2023]
Abstract
Despite significant advances in cancer therapeutics, chemotherapy remains the cornerstone of treatment for many tumors. Importantly, however, chemotherapy-induced toxicity, including hepatotoxicity, can lead to the interruption or discontinuation of potentially effective therapy. In recent years, special attention has been paid to the search for complementary therapies to mitigate chemotherapy-induced toxicity. Although there is currently a lack of specific interventions to mitigate or prevent hepatotoxicity in chemotherapy-treated patients, the polyphenol compound curcumin has emerged as a potential strategy to overcome this adverse effect. Here we review, firstly, the molecular and physiological mechanisms and major risk factors of chemotherapy-induced hepatotoxicity. We then present an overview of how curcumin has the potential to mitigate hepatotoxicity by targeting specific molecular mechanisms. Hepatotoxicity is a well-described side effect of cytotoxic drugs that can limit their clinical application. Inflammation and oxidative stress are the most common mechanisms involved in hepatotoxicity. Several studies have shown that curcumin could prevent and/or palliate chemotherapy-induced liver injury, mainly due to its anti-inflammatory, antioxidant, antifibrotic and hypolipidemic properties. Further clinical investigation using bioavailable curcumin formulations is warranted to demonstrate its efficacy as an hepatoprotective agent in cancer patients.
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Affiliation(s)
- Vicenç Ruiz de Porras
- Grup de Recerca en Toxicologia (GRET), Unitat de Toxicologia, Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Avda Joan XXIII s/n, 08028 Barcelona, Spain; CARE program, Germans Trias i Pujol Research Institute (IGTP), Camí de les Escoles, s/n, 08916, Badalona, Barcelona, Spain; Catalan Institute of Oncology, Badalona Applied Research Group in Oncology (B·ARGO), Camí de les Escoles, s/n, 08916, Badalona, Barcelona, Spain.
| | - Mariona Figols
- Medical Oncology Department, Althaia Xarxa Assistencial Universitària de Manresa, C/ Dr. Joan Soler, 1-3, 08243, Manresa, Barcelona, Spain
| | - Albert Font
- CARE program, Germans Trias i Pujol Research Institute (IGTP), Camí de les Escoles, s/n, 08916, Badalona, Barcelona, Spain; Catalan Institute of Oncology, Badalona Applied Research Group in Oncology (B·ARGO), Camí de les Escoles, s/n, 08916, Badalona, Barcelona, Spain; Medical Oncology Department, Catalan Institute of Oncology, Camí de les Escoles, s/n, 08916, Badalona, Barcelona, Spain
| | - Eva Pardina
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Diagonal 643, 08028 Barcelona, Spain.
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15
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Gruneau L, Kechagias S, Sandström P, Ekstedt M, Henriksson M. Cost-effectiveness analysis of noninvasive tests to identify advanced fibrosis in non-alcoholic fatty liver disease. Hepatol Commun 2023; 7:e00191. [PMID: 37347223 PMCID: PMC10289790 DOI: 10.1097/hc9.0000000000000191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 05/08/2023] [Indexed: 06/23/2023] Open
Abstract
BACKGROUND Advanced fibrosis is associated with end-stage liver disease (ESLD) and mortality in NAFLD. As treatments specifically targeted at NAFLD are lacking, patient management focuses on surveillance for early detection of complications related to end-stage liver disease. Although current and emerging diagnostic tools for the detection of advanced fibrosis are crucial for surveillance, their added value is unclear. The aim of this study was to evaluate the costs and health outcomes of noninvasive tests in patient management strategies for diagnosing advanced fibrosis in NAFLD patients. METHOD A decision analytical model was developed to evaluate 13 patient management strategies, including a no-testing strategy and 12 diagnostic algorithms with noninvasive tests (fibrosis 4- score, enhanced liver fibrosis, vibration controlled transient elastography), and liver biopsy. Model inputs were synthesized from the literature and Swedish registries. Lifetime health care costs, life years, quality-adjusted life years, clinical outcomes, and incremental cost-effectiveness ratios were calculated for a cohort of 55-year-old patients diagnosed with NAFLD. RESULT The cost per quality-adjusted life year was above €50 000 for all diagnostic algorithms compared to no-testing. The cost per quality-adjusted life year of the most promising diagnostic algorithm (fibrosis 4- score, enhanced liver fibrosis, vibration controlled transient elastography, and liver biopsy) was ∼ €181 000 compared with no testing. Sensitivity analysis indicated that if treatment slowed down disease progression, the value of testing increased. CONCLUSION The result questions the overall value of comprehensive diagnostic testing in a broad NAFLD population in current routine clinical care. The role of noninvasive tests may change if evidence-based treatments to slow down disease progression emerge.
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Affiliation(s)
- Lina Gruneau
- Center for Medical Technology Assessment, Department of Health, Medicine and Caring Sciences, Linköping University, Sweden
| | - Stergios Kechagias
- Division of Diagnostics and Specialist Medicine, Department of Health, and Caring Sciences, Linköping University, Sweden
| | - Per Sandström
- Division of Surgery, Department of Biomedical and Clinical Sciences, Orthopedics, and Oncology, Linköping University, Sweden
| | - Mattias Ekstedt
- Division of Diagnostics and Specialist Medicine, Department of Health, and Caring Sciences, Linköping University, Sweden
- Center for Medical Image Science and Visualization, Linköping University, Linköping, Sweden
| | - Martin Henriksson
- Center for Medical Technology Assessment, Department of Health, Medicine and Caring Sciences, Linköping University, Sweden
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16
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Ganesan R, Gupta H, Jeong JJ, Sharma SP, Won SM, Oh KK, Yoon SJ, Kim DJ, Suk KT. A metabolomics approach to the validation of predictive metabolites and phenotypic expression in non-alcoholic fatty liver disease. Life Sci 2023; 322:121626. [PMID: 37003543 DOI: 10.1016/j.lfs.2023.121626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/15/2023] [Accepted: 03/23/2023] [Indexed: 04/03/2023]
Abstract
AIMS Nonalcoholic fatty liver disease (NAFLD) is becoming more common and severe. Individuals with NAFLD have an altered composition of gut- microbial metabolites. We used metabolomics profiling to identify microbial metabolites that could indicate gut-liver metabolic severity. Noninvasive biomarkers are required for NAFLD, especially for patients at high risk of disease progression. MAIN METHODS We compared the stool metabolomes, untargeted metabolomics, and clinical data of 80 patients. Patients with nonalcoholic fatty liver (NAFL: n = 16), nonalcoholic steatohepatitis (NASH: n = 26), and cirrhosis (n = 19) and healthy control individuals (HC: n = 19) were enrolled. The identified metabolites in NAFLD were evaluated by multivariate statistical analysis and metabolic pathotypic expression. Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography coupled to time-of-flight-mass spectrometry (LC-TOF-MS) were used to analyze metabolites. KEY FINDINGS Untargeted metabolomics was used to identify and quantify 103 metabolites. Principal component analysis (PCA) was used to assess the metabolic discrimination of NAFL, NASH, and cirrhosis. Short-chain fatty acids (SCFA) levels were significantly lower in NAFLD patients, including those of acetate (p = 0.03), butyrate (p = 0.0008), and propionate. The stool cholic acid (p = 0.001) level was significantly increased in NAFLD patients. Palmitoylcarnitine and l-carnitine levels were significantly increased in NASH and cirrhosis patients. The phenotypic expression of these metabolites was linked to β-oxidation. SIGNIFICANCE We demonstrated a distinct metabolome profile in NAFLD patients with NAFL, NASH, and cirrhosis. We also discovered that the expression of certain metabolites and metabolic pathways was linked to NAFLD.
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Affiliation(s)
- Raja Ganesan
- Institute for Liver and Digestive Diseases, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Haripriya Gupta
- Institute for Liver and Digestive Diseases, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Jin-Ju Jeong
- Institute for Liver and Digestive Diseases, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Satya Priya Sharma
- Institute for Liver and Digestive Diseases, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Sung-Min Won
- Institute for Liver and Digestive Diseases, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Ki-Kwang Oh
- Institute for Liver and Digestive Diseases, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Sang Jun Yoon
- Institute for Liver and Digestive Diseases, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Dong Joon Kim
- Institute for Liver and Digestive Diseases, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Ki Tae Suk
- Institute for Liver and Digestive Diseases, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
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Spann A, Bishop KM, Weitkamp AO, Stenner SP, Nelson SD, Izzy M. Clinical decision support automates care gap detection among primary care patients with nonalcoholic fatty liver disease. Hepatol Commun 2023; 7:e0035. [PMID: 36757410 PMCID: PMC9915945 DOI: 10.1097/hc9.0000000000000035] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 11/10/2022] [Indexed: 02/10/2023] Open
Abstract
BACKGROUND Although guidelines recommend primary care-driven management of NAFLD, workflow constraints hinder feasibility. Leveraging electronic health records to risk stratify patients proposes a scalable, workflow-integrated strategy. MATERIALS AND METHODS We prospectively evaluated an electronic health record-embedded clinical decision support system's ability to risk stratify patients with NAFLD and detect gaps in care. Patients missing annual laboratory testing to calculate Fibrosis-4 Score (FIB-4) or those missing necessary linkage to further care were considered to have a gap in care. Linkage to care was defined as either referral for elastography-based testing or for consultation in hepatology clinic depending on clinical and biochemical characteristics. RESULTS Patients with NAFLD often lacked annual screening labs within primary care settings (1129/2154; 52%). Linkage to care was low in all categories, with <3% of patients with abnormal FIB-4 undergoing further evaluation. DISCUSSION Significant care gaps exist within primary care for screening and risk stratification of patients with NAFLD and can be efficiently addressed using electronic health record functionality.
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Affiliation(s)
- Ashley Spann
- Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Kristy M. Bishop
- Department of HealthIT, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Asli O. Weitkamp
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Shane P. Stenner
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Scott D. Nelson
- Department of HealthIT, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Manhal Izzy
- Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Kalafati IP, Dimitriou M, Revenas K, Kokkinos A, Deloukas P, Dedoussis GV. TM6SF2-rs58542926 Genetic Variant Modifies the Protective Effect of a "Prudent" Dietary Pattern on Serum Triglyceride Levels. Nutrients 2023; 15:1112. [PMID: 36904112 PMCID: PMC10005630 DOI: 10.3390/nu15051112] [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: 01/29/2023] [Revised: 02/18/2023] [Accepted: 02/21/2023] [Indexed: 02/25/2023] Open
Abstract
The epidemic prevalence of non-alcoholic fatty liver disease (NAFLD), despite extensive research in the field, underlines the importance of focusing on personalized therapeutic approaches. However, nutrigenetic effects on NAFLD are poorly investigated. To this end, we aimed to explore potential gene-dietary pattern interactions in a NAFLD case-control study. The disease was diagnosed with liver ultrasound and blood collection was performed after an overnight fast. Adherence to four a posteriori, data-driven, dietary patterns was used to investigate interactions with PNPLA3-rs738409, TM6SF2-rs58542926, MBOAT7-rs641738, and GCKR-rs738409 in disease and related traits. IBM SPSS Statistics/v21.0 and Plink/v1.07 were used for statistical analyses. The sample consisted of 351 Caucasian individuals. PNPLA3-rs738409 was positively associated with disease odds (OR = 1.575, p = 0.012) and GCKR-rs738409 with lnC-reactive protein (CRP) (beta = 0.098, p = 0.003) and Fatty Liver Index (FLI) levels (beta = 5.011, p = 0.007). The protective effect of a "Prudent" dietary pattern on serum triglyceride (TG) levels in this sample was significantly modified by TM6SF2-rs58542926 (pinteraction = 0.007). TM6SF2-rs58542926 carriers may not benefit from a diet rich in unsaturated fatty acids and carbohydrates in regard to TG levels, a commonly elevated feature in NAFLD patients.
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Affiliation(s)
- Ioanna Panagiota Kalafati
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, 17671 Athens, Greece
- Department of Nutrition and Dietetics, School of Physical Education, Sport Science and Dietetics, University of Thessaly, 42100 Trikala, Greece
| | - Maria Dimitriou
- Department of Nutrition and Dietetics, School of Health Sciences, University of the Peloponnese, Antikalamos, 24100 Kalamata, Greece
| | | | - Alexander Kokkinos
- First Department of Propaedeutic Medicine, School of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece
| | - Panos Deloukas
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - George V. Dedoussis
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, 17671 Athens, Greece
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19
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Wu Y, Liu Q, Wang Y, Li F, Chan LWC, Wen Y, Yang F, Xiang Y, Duan Q, Luo P, Lei P. Diagnostic efficiency on ultrasound shear wave elastography in evaluation of steatosis severity for non-alcoholic fatty liver disease: a rat model. Eur J Med Res 2023; 28:75. [PMID: 36774529 PMCID: PMC9921353 DOI: 10.1186/s40001-023-01042-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 02/03/2023] [Indexed: 02/13/2023] Open
Abstract
BACKGROUND The pathological feature of steatosis affects the elasticity values measured by shear wave elastography (SWE) is still controversial in non-alcoholic fatty liver disease (NAFLD). The aim of this study is to demonstrate the influence of steatosis on liver stiffness measured by SWE on a rat model with NAFLD and analyze feasibility of SWE for grading steatosis in absence of fibrosis. METHODS Sixty-six rats were fed with methionine choline deficient diet or standard diet to produce various stages of steatosis; 48 rats were available for final analysis. Rats underwent abdominal ultrasound SWE examination and pathological assessment. Liver histopathology was analyzed to assess the degree of steatosis, inflammation, ballooning, and fibrosis according to the non-alcoholic fatty liver disease activity score. The diagnostic performance of SWE for differentiating steatosis stages was estimated according to the receiver operating characteristic (ROC) curve. Decision curve analysis (DCA) was conducted to determine clinical usefulness and the areas under DCA (AUDCAs) calculated. RESULTS In multivariate analysis, steatosis was an independent factor affecting the mean elastic modules (B = 1.558, P < 0.001), but not inflammation (B = - 0.031, P = 0.920) and ballooning (B = 0.216, P = 0.458). After adjusting for inflammation and ballooning, the AUROC of the mean elasticity for identifying S ≥ S1 was 0.956 (95%CI: 0.872-0.998) and the AUDCA, 0.621. The AUROC for distinguishing S ≥ S2 and S = S3 was 0.987 (95%CI: 0.951-1.000) and 0.920 (95%CI: 0.816-0.986) and the AUDCA was 0.506 and 0.256, respectively. CONCLUSIONS Steatosis is associated with liver stiffness and SWE may have the feasibility to be introduced as an assistive technology in grading steatosis for patients with NAFLD in absence of fibrosis.
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Affiliation(s)
- Yuhui Wu
- grid.452244.1Department of Radiology, the Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Yunyan District, Guiyang, 550004 Guizhou China
| | - Qianjiao Liu
- grid.452244.1Department of Radiology, the Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Yunyan District, Guiyang, 550004 Guizhou China
| | - Yan Wang
- grid.452244.1Department of Radiology, the Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Yunyan District, Guiyang, 550004 Guizhou China
| | - Fangyan Li
- grid.452244.1Department of Radiology, the Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Yunyan District, Guiyang, 550004 Guizhou China
| | - Lawrence Wing-Chi Chan
- grid.16890.360000 0004 1764 6123Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, SAR China
| | - Yong Wen
- grid.452244.1Department of Radiology, the Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Yunyan District, Guiyang, 550004 Guizhou China
| | - Fan Yang
- grid.413458.f0000 0000 9330 9891School of Biology & Engineering, Guizhou Medical University, Guiyang,, Guizhou China
| | - Yining Xiang
- grid.452244.1Department of Pathology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou China
| | - Qinghong Duan
- grid.452244.1Department of Radiology, the Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Yunyan District, Guiyang, 550004 Guizhou China
| | - Peng Luo
- grid.413458.f0000 0000 9330 9891School of Public Health, Guizhou Medical University, Guiyang, Guizhou China
| | - Pinggui Lei
- Department of Radiology, the Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Yunyan District, Guiyang, 550004, Guizhou, China. .,School of Public Health, Guizhou Medical University, Guiyang, Guizhou, China. .,Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, SAR, China.
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20
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Monirujjaman M, Renani LB, Isesele P, Dunichand-Hoedl AR, Mazurak VC. Increased Expression of Hepatic Stearoyl-CoA Desaturase (SCD)-1 and Depletion of Eicosapentaenoic Acid (EPA) Content following Cytotoxic Cancer Therapy Are Reversed by Dietary Fish Oil. Int J Mol Sci 2023; 24:ijms24043547. [PMID: 36834959 PMCID: PMC9962117 DOI: 10.3390/ijms24043547] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/03/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
Cancer treatment evokes impediments to liver metabolism that culminate in fatty liver. This study determined hepatic fatty acid composition and expression of genes and mediators involved in lipid metabolism following chemotherapy treatment. Female rats bearing the Ward colon tumor were administered Irinotecan (CPT-11) +5-fluorouracil (5-FU) and maintained on a control diet or a diet containing eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) (2.3 g/100 g fish oil). Healthy animals provided with a control diet served as a reference group. Livers were collected one week after chemotherapy. Triacylglycerol (TG), phospholipid (PL), ten lipid metabolism genes, leptin, and IL-4 were measured. Chemotherapy increased TG content and reduced EPA content in the liver. Expression of SCD1 was upregulated by chemotherapy, while dietary fish oil downregulated its expression. Dietary fish oil down-regulated expression of the fatty acid synthesis gene FASN, while restoring the long chain fatty acid converting genes FADS2 and ELOVL2, and genes involved in mitochondrial β-oxidation (CPT1α) and lipid transport (MTTP1), to values similar to reference animals. Neither leptin nor IL-4 were affected by chemotherapy or diet. Depletion of EPA is associated with pathways evoking enhanced TG accumulation in the liver. Restoring EPA through diet may pose a dietary strategy to attenuate chemotherapy-associated impediments in liver fatty acid metabolism.
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21
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Higgins CB, Adams JA, Ward MH, Greenberg ZJ, Milewska M, Sun J, Zhang Y, Chiquetto Paracatu L, Dong Q, Ballentine S, Li W, Wandzik I, Schuettpelz LG, DeBosch BJ. The tetraspanin transmembrane protein CD53 mediates dyslipidemia and integrates inflammatory and metabolic signaling in hepatocytes. J Biol Chem 2023; 299:102835. [PMID: 36581203 PMCID: PMC9900517 DOI: 10.1016/j.jbc.2022.102835] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 12/14/2022] [Accepted: 12/18/2022] [Indexed: 12/28/2022] Open
Abstract
Tetraspanins are transmembrane signaling and proinflammatory proteins. Prior work demonstrates that the tetraspanin, CD53/TSPAN25/MOX44, mediates B-cell development and lymphocyte migration to lymph nodes and is implicated in various inflammatory diseases. However, CD53 is also expressed in highly metabolic tissues, including adipose and liver; yet its function outside the lymphoid compartment is not defined. Here, we show that CD53 demarcates the nutritional and inflammatory status of hepatocytes. High-fat exposure and inflammatory stimuli induced CD53 in vivo in liver and isolated primary hepatocytes. In contrast, restricting hepatocyte glucose flux through hepatocyte glucose transporter 8 deletion or through trehalose treatment blocked CD53 induction in fat- and fructose-exposed contexts. Furthermore, germline CD53 deletion in vivo blocked Western diet-induced dyslipidemia and hepatic inflammatory transcriptomic activation. Surprisingly, metabolic protection in CD53 KO mice was more pronounced in the presence of an inciting inflammatory event. CD53 deletion attenuated tumor necrosis factor alpha-induced and fatty acid + lipopolysaccharide-induced cytokine gene expression and hepatocyte triglyceride accumulation in isolated murine hepatocytes. In vivo, CD53 deletion in nonalcoholic steatohepatitis diet-fed mice blocked peripheral adipose accumulation and adipose inflammation, insulin tolerance, and liver lipid accumulation. We then defined a stabilized and trehalase-resistant trehalose polymer that blocks hepatocyte CD53 expression in basal and over-fed contexts. The data suggest that CD53 integrates inflammatory and metabolic signals in response to hepatocyte nutritional status and that CD53 blockade may provide a means by which to attenuate pathophysiology in diseases that integrate overnutrition and inflammation, such as nonalcoholic steatohepatitis and type 2 diabetes.
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Affiliation(s)
- Cassandra B Higgins
- Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA
| | - Joshua A Adams
- Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA
| | - Matthew H Ward
- Department of Chemistry, Washington University in St Louis, St Louis, Missouri, USA
| | - Zev J Greenberg
- Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA
| | - Małgorzata Milewska
- Biotechnology Center, Silesian University of Technology, Gliwice, Poland; Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, Silesian University of Technology, Gliwice, Poland
| | - Jiameng Sun
- Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA
| | - Yiming Zhang
- Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA
| | | | - Qian Dong
- Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA
| | - Samuel Ballentine
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Weikai Li
- Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St Louis, Missouri, USA
| | - Ilona Wandzik
- Biotechnology Center, Silesian University of Technology, Gliwice, Poland; Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, Silesian University of Technology, Gliwice, Poland
| | - Laura G Schuettpelz
- Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA; Siteman Cancer Center, Washington University, St. Louis, Missouri, USA
| | - Brian J DeBosch
- Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA; Department of Cell Biology & Physiology, Washington University School of Medicine, St Louis, Missouri, USA.
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22
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Gruneau L, Ekstedt M, Kechagias S, Henriksson M. Disease Progression Modeling for Economic Evaluation in Nonalcoholic Fatty Liver Disease-A Systematic Review. Clin Gastroenterol Hepatol 2023; 21:283-298. [PMID: 34757199 DOI: 10.1016/j.cgh.2021.10.040] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 09/10/2021] [Accepted: 10/24/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Globally, 25% of people have nonalcoholic fatty liver disease (NAFLD), and, currently, there are no approved pharmacologic treatments for NAFLD. With a slow disease progression, long-term impact of pharmacologic treatments can be assessed only by complementing emerging clinical trial evidence with data from other sources in disease progression modeling. Although this modeling is crucial for economic evaluation studies assessing the clinical and economic consequences of new treatments, the approach to modeling the natural history of NAFLD differs in contemporary research. This systematic literature review investigated modeling of the natural history of NAFLD. METHODS A systematic literature review was conducted searching PubMed, Scopus, Cochrane, and the National Health Service Economic Evaluation Database to identify articles focusing on modeling of the natural history of NAFLD. Model structure and transition probabilities were extracted from included studies. RESULTS Of the 28 articles identified, differences were seen in model structure and data input. Clear definitions of nonalcoholic steatohepatitis and NAFLD often were lacking; differences in the granularity of modeling fibrosis progression, the approach to disease regression, and modeling of advanced liver disease varied across studies. Observed transition probabilities for F0 to F1, F1 to F2, F2 to F3, and F3 to compensated cirrhosis varied between 0.059 to 0.095, 0.023 to 0.140, 0.018 to 0.070, and 0.040 to 0.118, respectively. CONCLUSIONS The difference in disease progression modeling for seemingly similar models warrants further inquiry regarding how to model the natural course of NAFLD. Such differences may have a large impact when assessing the value of emerging pharmacologic treatments.
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Affiliation(s)
- Lina Gruneau
- Center for Medical Technology Assessment, Linköping, Sweden.
| | - Mattias Ekstedt
- Division of Diagnostics and Specialist Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Stergios Kechagias
- Division of Diagnostics and Specialist Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
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23
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Xie CH, Chen LW, Lin CL, Hu CC, Chien CH. Serum Uric Acid but Not Ferritin Level Is Associated with Hepatic Fibrosis in Lean Subjects with Metabolic Dysfunction-Associated Fatty Liver Disease: A Community-Based Study. J Pers Med 2022; 12:jpm12122009. [PMID: 36556230 PMCID: PMC9782820 DOI: 10.3390/jpm12122009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 11/27/2022] [Accepted: 12/01/2022] [Indexed: 12/09/2022] Open
Abstract
Elevated serum ferritin and uric acid levels are common in patients with fatty liver disease. This study assessed the association between serum ferritin and uric acid levels and liver fibrosis in subjects with lean metabolic dysfunction-associated fatty liver disease (MAFLD). This cross-sectional study used data from a community screening examination for metabolic syndrome from December 2018 to September 2019 at Keelung Chang Gung Memorial Hospital. Subjects with lean MAFLD were defined as those with a body mass index (BMI) < 23 kg/m2 and hepatic steatosis according to the MAFLD criteria. A total of 182 lean subjects were included and were divided into lean MAFLD and lean healthy groups. Serum ferritin and uric acid concentrations were positively correlated with liver fibrosis, regardless of whether FIB-4, APRI, or NFS were used as references. Univariate logistic regression analysis showed that age and uric acid were associated with advanced liver fibrosis. After adjusting for potential confounders, only uric acid level was statistically significant in predicting the advanced liver fibrosis (OR = 6.907 (1.111−42.94), p = 0.038) in the lean MAFLD group. We found that an elevated serum uric acid level is an independent factor associated with advanced liver fibrosis in lean MAFLD subjects by noninvasive fibrosis scores.
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Affiliation(s)
- Cheng-Han Xie
- Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital and University, Keelung 204, Taiwan
| | - Li-Wei Chen
- Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital and University, Keelung 204, Taiwan
- Community Medicine Research Center, Chang-Gung Memorial Hospital and University, Keelung 204, Taiwan
- Correspondence: ; Tel.: +886-2-24313131 (ext. 6203); Fax: +886-2-24335342
| | - Chih-Lang Lin
- Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital and University, Keelung 204, Taiwan
- Community Medicine Research Center, Chang-Gung Memorial Hospital and University, Keelung 204, Taiwan
| | - Ching-Chih Hu
- Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital and University, Keelung 204, Taiwan
- Community Medicine Research Center, Chang-Gung Memorial Hospital and University, Keelung 204, Taiwan
| | - Cheng-Hung Chien
- Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital and University, Keelung 204, Taiwan
- Community Medicine Research Center, Chang-Gung Memorial Hospital and University, Keelung 204, Taiwan
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24
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Liu Q, Zhao G, Li Q, Wu W, Zhang Y, Bian H. A comparison of NAFLD and MAFLD diagnostic criteria in contemporary urban healthy adults in China: a cross-sectional study. BMC Gastroenterol 2022; 22:471. [PMID: 36402947 PMCID: PMC9675196 DOI: 10.1186/s12876-022-02576-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 11/14/2022] [Indexed: 11/21/2022] Open
Abstract
Background A recently proposed diagnostic criteria of metabolic dysfunction-associated fatty liver disease (MAFLD) is more available for various clinical situations than nonalcoholic fatty liver disease (NAFLD), but understanding about differences between NAFLD and MAFLD in clinical practice remains limited in the general adult urban population in China. Methods A total of 795 subjects were recruited from Wu Song Branch of Zhongshan Hospital who participated in the general health assessment. Examination results was obtained through analysis of blood samples and abdominal ultrasonography. Participants were divided into four subgroups according to whether they had NAFLD or MAFLD (NAFLD- MAFLD-, NAFLD + MAFLD-, NAFLD- MAFLD + and NAFLD + MAFLD+). Results Among the urban healthy adults investigated, 345 people (43.4%) were diagnosed with NAFLD and 356 people (44.8%) with MAFLD. No significant differences in the prevalence, age, fasting blood glucose, glycosylated hemoglobin, liver enzyme examination, percentage of overweight, hypertension or dyslipidaemia were found between NAFLD and MAFLD patients. Patients with MAFLD had worse metabolic disorders than NAFLD + MAFLD- patients. The NAFLD fibrosis score (NFS) of the NAFLD- MAFLD + group was higher than that of the NAFLD + MAFLD- group. Higher proportion of patients in the NAFLD- MAFLD + group have NFS ≥-1.455. Conclusion MAFLD criteria have similar prevalence and patient characteristics compared with previous NAFLD but help to identify a group of patients with high risks of metabolic disorders and liver fibrosis who have been missed with NAFLD, and has superior utility.
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25
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Yepmo M, Potier JB, Pinget M, Grabarz A, Bouzakri K, Dumond Bourie A. Discussing the role of circular RNA in the pathogenesis of non-alcoholic fatty liver disease and its complications. Front Endocrinol (Lausanne) 2022; 13:1035159. [PMID: 36407314 PMCID: PMC9667057 DOI: 10.3389/fendo.2022.1035159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 10/17/2022] [Indexed: 01/24/2023] Open
Abstract
Circular RNAs (circRNAs) are class of non-coding RNA, which are characterized by a covalently closed loop structure. Functionally they can act on cellular physiology, notably by sponging microRNAs (miR), regulating gene expression or interacting with binding protein. To date, circRNAs might represent an interesting, underexploited avenue for new target discovery for therapeutic applications, especially in the liver. The first characteristic of non-alcoholic fatty liver disease (NAFLD) is hepatic cholesterol accumulation, followed by its advanced form of the affection, nonalcoholic steatohepatitis (NASH), due to the occurrence of lobular inflammation, irreversible fibrosis, and in some cases hepatocellular carcinoma (HCC). Therefore, studies have investigated the importance of the dysregulation of circRNAs in the onset of metabolic disorders. In this review, we summarize the potential role of circRNAs in the development of metabolic diseases associated with the liver such as NAFLD or NASH, and their potential to become therapeutic strategies for these pathologies.
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Affiliation(s)
- Melissa Yepmo
- Centre européen d’étude du Diabète, Unité Mixte de Recherche de l’Université de Strasbourg « Diabète et Thérapeutique », Strasbourg, France
| | - Jean-Baptiste Potier
- Centre européen d’étude du Diabète, Unité Mixte de Recherche de l’Université de Strasbourg « Diabète et Thérapeutique », Strasbourg, France
- ILONOV, Strasbourg, France
| | - Michel Pinget
- Centre européen d’étude du Diabète, Unité Mixte de Recherche de l’Université de Strasbourg « Diabète et Thérapeutique », Strasbourg, France
| | | | - Karim Bouzakri
- Centre européen d’étude du Diabète, Unité Mixte de Recherche de l’Université de Strasbourg « Diabète et Thérapeutique », Strasbourg, France
- ILONOV, Strasbourg, France
| | - Aurore Dumond Bourie
- Centre européen d’étude du Diabète, Unité Mixte de Recherche de l’Université de Strasbourg « Diabète et Thérapeutique », Strasbourg, France
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Ivashkin VT, Maevskaya MV, Zharkova MS, Kotovskaya YV, Tkacheva ON, Troshina EA, Shestakova MV, Maev IV, Breder VV, Gheivandova NI, Doshchitsin VL, Dudinskaya EN, Ershova EV, Kodzoeva KB, Komshilova KA, Korochanskaya NV, Mayorov AY, Mishina EE, Nadinskaya MY, Nikitin IG, Pogosova NV, Tarzimanova AI, Shamkhalova MS. Clinical Practice Guidelines of the Russian Scientific Liver Society, Russian Gastroenterological Association, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians and National Society for Preventive Cardiology on Diagnosis and Treatment of Non-Alcoholic Liver Disease. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2022; 32:104-140. [DOI: 10.22416/1382-4376-2022-32-4-104-140] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Aim:present clinical guidelines, aimed at general practitioners, gastroenterologists, cardiologists, endocrinologists, comprise up-to-date methods of diagnosis and treatment of non-alcoholic fatty liver disease.Key points.Nonalcoholic fatty liver disease, the most wide-spread chronic liver disease, is characterized by accumulation of fat by more than 5 % of hepatocytes and presented by two histological forms: steatosis and nonalcoholic steatohepatitis. Clinical guidelines provide current views on pathogenesis of nonalcoholic fatty liver disease as a multisystem disease, methods of invasive and noninvasive diagnosis of steatosis and liver fibrosis, principles of nondrug treatment and pharmacotherapy of nonalcoholic fatty liver disease and associated conditions. Complications of nonalcoholic fatty liver disease include aggravation of cardiometabolic risks, development of hepatocellular cancer, progression of liver fibrosis to cirrhotic stage.Conclusion.Progression of liver disease can be avoided, cardiometabolic risks can be reduced and patients' prognosis — improved by the timely recognition of diagnosis of nonalcoholic fatty liver disease and associated comorbidities and competent multidisciplinary management of these patients.
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Affiliation(s)
| | | | | | - Yu. V. Kotovskaya
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
| | - O. N. Tkacheva
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
| | | | | | - I. V. Maev
- Yevdokimov Moscow State University of Medicine and Dentistry
| | - V. V. Breder
- Blokhin National Medical Research Center of Oncology
| | | | | | - E. N. Dudinskaya
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
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Vijayakumar A, Okesli-Armlovich A, Wang T, Olson I, Seung M, Kusam S, Hollenback D, Mahadevan S, Marchand B, Toteva M, Breckenridge DG, Trevaskis JL, Bates J. Combinations of an acetyl CoA carboxylase inhibitor with hepatic lipid modulating agents do not augment antifibrotic efficacy in preclinical models of NASH and fibrosis. Hepatol Commun 2022; 6:2298-2309. [PMID: 35735253 PMCID: PMC9426400 DOI: 10.1002/hep4.2011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 04/17/2022] [Accepted: 05/01/2022] [Indexed: 11/11/2022] Open
Abstract
Dysregulated hepatocyte lipid metabolism is a hallmark of hepatic lipotoxicity and contributes to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl CoA carboxylase (ACC) inhibitors decrease hepatocyte lipotoxicity by inhibiting de novo lipogenesis and concomitantly increasing fatty acid oxidation (FAO), and firsocostat, a liver‐targeted inhibitor of ACC1/2, is under evaluation clinically in patients with NASH. ACC inhibition is associated with improvements in indices of NASH and reduced liver triglyceride (TG) content, but also increased circulating TG in subjects with NASH and preclinical rodent models. Here we evaluated whether enhancing hepatocyte FAO by combining ACC inhibitors with peroxisomal proliferator‐activated receptor (PPAR) or thyroid hormone receptor beta (THRβ) agonists could drive greater liver TG reduction and NASH/antifibrotic efficacy, while ameliorating ACC inhibitor–induced hypertriglyceridemia. In high‐fat diet–fed dyslipidemic rats, the addition of PPAR agonists fenofibrate (Feno), elafibranor (Ela), lanifibranor (Lani), seladelpar (Sela) or saroglitazar (Saro), or the THRb agonist resmetirom (Res), to an analogue of firsocostat (ACCi) prevented ACCi‐induced hypertriglyceridemia. However, only PPARα agonists (Feno and Ela) and Res provided additional liver TG reduction. In the choline‐deficient high‐fat diet rat model of advanced liver fibrosis, neither PPARα (Feno) nor THRβ (Res) agonism augmented the antifibrotic efficacy of ACCi. Conclusion: These data suggest that combination therapies targeting hepatocyte lipid metabolism may have beneficial effects on liver TG reduction; however, they may not be sufficient to drive fibrosis regression.
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Affiliation(s)
| | | | - Ting Wang
- Gilead Sciences, Foster City, California, USA
| | | | - Minji Seung
- Gilead Sciences, Foster City, California, USA
| | | | | | | | | | | | | | | | - Jamie Bates
- Gilead Sciences, Foster City, California, USA
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Hakkak R, Spray B, Børsheim E, Korourian S. Diet Containing Soy Protein Concentrate With Low and High Isoflavones for 9 Weeks Protects Against Non-alcoholic Fatty Liver Steatosis Using Obese Zucker Rats. Front Nutr 2022; 9:913571. [PMID: 35811988 PMCID: PMC9258741 DOI: 10.3389/fnut.2022.913571] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 05/25/2022] [Indexed: 12/05/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), is one of the main liver diseases in the US and the world which often is related to obesity. Previously, we reported short- and long-term consumption of soy protein isolate diet with high isoflavones can reduce liver steatosis in the male and female obese Zucker rat model. However, the effects of high vs. low soy isoflavones on NAFLD is less known. The objectives of the present study were to examine the role of isoflavones levels in soy protein concentrate diets on protection against NAFLD in an obese rat model. Forty-two 6-week old lean (L, n = 21) and obese (O, n = 21) Zucker rats were randomly assigned to 1 of 3 dietary groups: casein diet (C = control), soy protein concentrate with low isoflavones (LIF), or soy protein concentrate with high isoflavones (HIF) for 9 weeks. Rats were weighed twice weekly. After 9 weeks, rats were sacrificed and samples of livers were taken for histopathological analysis. Serums were collected to measure ALT and AST levels. Results indicate that obese rats gained significantly more weight than lean rats for all three diet groups (P < 0.001). No significant difference in body weight between LC, LLIF and LHIF was noted. However, the OLIF and OHIF rats gained significantly more weight than OC rats (P < 0.001). Liver steatosis scores were significantly greater in obese rats compared to lean rats (P < 0.001). The OLIF and OHIF-fed rats had significantly reduced steatosis scores than OC rats (P = 0.013 and P < 0.001, respectively). The serum ALT levels were significantly greater in OC, OLIF and OHIF compared to LC, LLIF and LHIF, respectively (P < 0.001, P < 0.001, and P = 0.011). AST serum levels were greater in OC and OLIF compared to LC and LLIF, respectively (P = 0.001 and P = 0.022). In summary, we found that soy protein concentrate with isoflavones protects against liver steatosis and the protection is greater with a higher concentration of isoflavones.
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Affiliation(s)
- Reza Hakkak
- Department of Dietetics and Nutrition, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Arkansas Children's Research Institute, Little Rock, AR, United States
- *Correspondence: Reza Hakkak
| | - Beverly Spray
- Arkansas Children's Research Institute, Little Rock, AR, United States
| | - Elisabet Børsheim
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Arkansas Children's Research Institute, Little Rock, AR, United States
- Arkansas Children's Nutrition Center, Little Rock, AR, United States
| | - Soheila Korourian
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, United States
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Sayegh NF, Heraoui GNHA, Younes H, Sayegh LN, Boulos C, Sayegh R. Relation of Dietary Patterns and Nutritional Profile to Hepatic Fibrosis in a Sample of Lebanese Non-Alcoholic Fatty Liver Disease Patients. Nutrients 2022; 14:nu14122554. [PMID: 35745284 PMCID: PMC9229197 DOI: 10.3390/nu14122554] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/15/2022] [Accepted: 06/17/2022] [Indexed: 11/16/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver injury worldwide. NAFLD can evolve into non-alcoholic steatohepatitis (NASH) with or without fibrosis. The objectives of this study were to determine the nutritional profile and dietary patterns of NAFLD Lebanese patients and to report the type of diet-related to the presence of hepatic fibrosis. We hypothesized that the traditional pattern was related to a low risk of fibrosis. This cross-sectional study included 320 eligible Lebanese NAFLD patients. Three dietary patterns were identified: the Traditional diet, the High Fruit diet, and the Westernized diet. Multivariate analysis showed a significant relationship between high adherence to the traditional diet and absence of hepatic fibrosis with a decreased risk of 82%, p = 0.031 after adjusting for its covariables. Fruits were absent from this dietary pattern. Although our results pointed to a possible relationship between fibrosis in NAFLD patients and fruit intake, experimental studies are needed to show whether this is a causal relationship. However, the results obtained in this study may contribute to the planning of dietary interventions and recommendations and enable a better follow-up for NAFLD patients with fibrosis.
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Affiliation(s)
- Nicole Fakhoury Sayegh
- Department of Nutrition, Faculty of Pharmacy, Saint Joseph University, Damascus Road, Riad el Solh, Beirut P.O. Box 11-5076, Lebanon; (G.N.H.A.H.); (C.B.)
- Correspondence: or
| | - Gessica N. H. A. Heraoui
- Department of Nutrition, Faculty of Pharmacy, Saint Joseph University, Damascus Road, Riad el Solh, Beirut P.O. Box 11-5076, Lebanon; (G.N.H.A.H.); (C.B.)
| | - Hassan Younes
- College Health, équipe PANASH-ULR 7519, Institut Polytechnique UniLaSalle, 19, Rue Pierre Waguet, CEDEX, 60026 Beauvais, France;
| | - Lea Nicole Sayegh
- Faculty of Medicine, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon;
| | - Christa Boulos
- Department of Nutrition, Faculty of Pharmacy, Saint Joseph University, Damascus Road, Riad el Solh, Beirut P.O. Box 11-5076, Lebanon; (G.N.H.A.H.); (C.B.)
| | - Raymond Sayegh
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saint Joseph University, Damascus Road, Riad el Solh, Beirut P.O. Box 11-5076, Lebanon;
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Zhong L, Peng X, Wu C, Li Q, Chen Y, Wang M, Li Y, He K, Shi Y, Bie C, Tang S. Polysaccharides and flavonoids from cyclocarya paliurus modulate gut microbiota and attenuate hepatic steatosis, hyperglycemia, and hyperlipidemia in nonalcoholic fatty liver disease rats with type 2 diabetes mellitus. Int J Diabetes Dev Ctries 2022. [DOI: 10.1007/s13410-022-01080-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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Maevskaya M, Kotovskaya Y, Ivashkin V, Tkacheva O, Troshina E, Shestakova M, Breder V, Geyvandova N, Doschitsin V, Dudinskaya E, Ershova E, Kodzoeva K, Komshilova K, Korochanskaya N, Mayorov A, Mishina E, Nadinskaya M, Nikitin I, Pogosova N, Tarzimanova A, Shamkhalova M. The National Consensus statement on the management of adult patients with non-alcoholic fatty liver disease and main comorbidities. TERAPEVT ARKH 2022; 94:216-253. [PMID: 36286746 DOI: 10.26442/00403660.2022.02.201363] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Indexed: 12/15/2022]
Abstract
The National Consensus was prepared with the participation of the National Medical Association for the Study of the Multimorbidity, Russian Scientific Liver Society, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians, National Society for Preventive Cardiology, Professional Foundation for the Promotion of Medicine Fund PROFMEDFORUM.
The aim of the multidisciplinary consensus is a detailed analysis of the course of non-alcoholic fatty liver disease (NAFLD) and the main associated conditions. The definition of NAFLD is given, its prevalence is described, methods for diagnosing its components such as steatosis, inflammation and fibrosis are described.
The association of NAFLD with a number of cardio-metabolic diseases (arterial hypertension, atherosclerosis, thrombotic complications, type 2 diabetes mellitus (T2DM), obesity, dyslipidemia, etc.), chronic kidney disease (CKD) and the risk of developing hepatocellular cancer (HCC) were analyzed. The review of non-drug methods of treatment of NAFLD and modern opportunities of pharmacotherapy are presented.
The possibilities of new molecules in the treatment of NAFLD are considered: agonists of nuclear receptors, antagonists of pro-inflammatory molecules, etc. The positive properties and disadvantages of currently used drugs (vitamin E, thiazolidinediones, etc.) are described. Special attention is paid to the multi-target ursodeoxycholic acid (UDCA) molecule in the complex treatment of NAFLD as a multifactorial disease. Its anti-inflammatory, anti-oxidant and cytoprotective properties, the ability to reduce steatosis an independent risk factor for the development of cardiovascular pathology, reduce inflammation and hepatic fibrosis through the modulation of autophagy are considered.
The ability of UDCA to influence glucose and lipid homeostasis and to have an anticarcinogenic effect has been demonstrated. The Consensus statement has advanced provisions for practitioners to optimize the diagnosis and treatment of NAFLD and related common pathogenetic links of cardio-metabolic diseases.
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Unsal İO, Calapkulu M, Sencar ME, Cakal B, Ozbek M. Evaluation of NAFLD fibrosis, FIB-4 and APRI score in diabetic patients receiving exenatide treatment for non-alcoholic fatty liver disease. Sci Rep 2022; 12:283. [PMID: 34997159 PMCID: PMC8741957 DOI: 10.1038/s41598-021-04361-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 12/13/2021] [Indexed: 02/07/2023] Open
Abstract
There is a closely relationship between the development and progression of nonalcoholic fatty liver disease (NAFLD) or metabolic associated fatty liver disease (MAFLD) and obesity and diabetes. NAFLD fibrosis scores should be routinely used to rule out patients with advanced fibrosis. High scores may help identify patients at higher risk of all causes andliverrelated morbidity and mortality. The aim of this study was to investigate the association between exenatide and fibrosis scores. The effect of exenatide treatment on fibrosis scores was evaluated in type 2 diabetes mellitus (DM) patients with MAFLD. Evaluation was made of 50 patients with type 2 DM and MAFLD. The NFS, FIB4 and APRI scores were calculated before and after 6 months of treatment. After 6 months of exenatide treatment, the NFS and APRI scores were determined to have decreased significantly. Exenatide was observed to control blood glucose, reduce body weight and improve fibrosis scores in MAFLD patients with type 2 diabetes.
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Affiliation(s)
- İlknur Ozturk Unsal
- Department of Endocrinology and Metabolism, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Sehit Omer Halisdemir Avenue, 06110, Ankara, Turkey.
| | - Murat Calapkulu
- Department of Endocrinology and Metabolism, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Sehit Omer Halisdemir Avenue, 06110, Ankara, Turkey
| | - Muhammed Erkam Sencar
- Department of Endocrinology and Metabolism, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Sehit Omer Halisdemir Avenue, 06110, Ankara, Turkey
| | - Basak Cakal
- Department of Gastroenterology, University of Health Sciences, Ankara Training and Research Hospital, Ankara, Turkey
| | - Mustafa Ozbek
- Department of Endocrinology and Metabolism, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Sehit Omer Halisdemir Avenue, 06110, Ankara, Turkey
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Silverman RB. Inactivators of Ornithine Aminotransferase for the Treatment of Hepatocellular Carcinoma. ACS Med Chem Lett 2021; 13:38-49. [PMID: 35059122 PMCID: PMC8762738 DOI: 10.1021/acsmedchemlett.1c00526] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 11/22/2021] [Indexed: 01/16/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the second or third leading cause of cancer mortality worldwide (depending on which statistics are used), yet there is no effective treatment. Currently, there are nine FDA-approved drugs for HCC, five monoclonal antibodies and four tyrosine kinase inhibitors. Ornithine aminotransferase (OAT) has been validated as a target in preclinical studies, which demonstrates that it is a potential target to treat HCC. Currently, there are no OAT inactivators in clinical trials for HCC. This Innovation describes evidence to support inhibition of OAT as a novel approach for HCC tumor growth inhibition. After the mechanism of OAT is discussed, the origins of our involvement in OAT inactivation, based on our previous work on mechanism-based inactivation of GABA-AT, are described. Once it was demonstrated that OAT inactivation does lead to HCC tumor growth inhibition, new selective OAT inactivators were designed and their inactivation mechanisms were elucidated. A summary of these mechanistic studies is presented. Inactivators of OAT provide the potential for treatment of HCC, targeting the Wnt/β-catenin pathway.
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Abbasi E, Vafaei SA, Naseri N, Darini A, Azandaryani MT, Ara FK, Mirzaei F. Protective effects of cerium oxide nanoparticles in non-alcoholic fatty liver disease (NAFLD) and carbon tetrachloride-induced liver damage in rats: Study on intestine and liver. Metabol Open 2021; 12:100151. [PMID: 34870139 PMCID: PMC8626579 DOI: 10.1016/j.metop.2021.100151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 11/04/2021] [Accepted: 11/05/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND AND AIMS Nanoparticles could represent a therapeutic approach for the treatment of various diseases. It has been reported that cerium oxide nanoparticles (CeO2 NPs) have potential useful effects. Therefore, we aimed to examine the protective effects of the CeO2 NPs in two models of liver injury, non-alcoholic fatty liver disease (NAFLD) and carbon tetrachloride (CCl4)-induced liver fibrosis, in rats. METHODS In this experimental study, male rats were randomly divided into different experimental groups including: Experiment 1; group1: healthy rats received normal saline, 2: CCl4 group, 3: CCl4 + nanoparticle. Experiment 2; group1: healthy rats received chow diet, 2: NAFLD group, 3: NAFLD + nanoparticle. The oxidative stress markers were determined in the liver and intestine. Tumor necrosis factor-α (TNF-α) levels were measured by ELISA. Histopathological changes of liver and intestine were evaluated by light microspore. RESULTS Total antioxidant capacity (TAC) and glutathione (GSH) levels significantly decreased, while malondialdehyde (MDA) and total oxidant status (TOS) were significantly increased in the liver, and intestine of the NAFLD and CCl4 group compared with control rats. However, the use of nanoparticles significantly normalized these markers. The levels of the TNF-α were significantly reduced in the nanoparticle group as compared with NAFLD model and CCl4-treated rats. CeO2 NPs also normalized the liver and intestinal histological changes. CONCLUSIONS Our finding revealed that CeO2 NPs has potential protective effects by increasing antioxidant activity, and reducing inflammation.
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Affiliation(s)
- Ebrahim Abbasi
- Department of Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | | | - Nima Naseri
- Department of Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ali Darini
- Department of Nanotechnology, Pharmaceutical Sciences Branch, Islamic Azad University (IAUPS), Tehran, Iran
| | | | - Farhad Kian Ara
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fatemeh Mirzaei
- Department of Anatomy, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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An GH, Lee J, Jin X, Chung J, Kim JC, Park JH, Kim M, Han C, Kim JH, Woo DH. Truncated Milk Fat Globule-EGF-like Factor 8 Ameliorates Liver Fibrosis via Inhibition of Integrin-TGFβ Receptor Interaction. Biomedicines 2021; 9:biomedicines9111529. [PMID: 34829758 PMCID: PMC8615163 DOI: 10.3390/biomedicines9111529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/27/2021] [Accepted: 10/21/2021] [Indexed: 11/16/2022] Open
Abstract
Milk fat globule-EGF factor 8 (MFG-E8) protein is known as an immunomodulator in various diseases, and we previously demonstrated the anti-fibrotic role of MFG-E8 in liver disease. Here, we present a truncated form of MFG-E8 that provides an advanced therapeutic benefit in treating liver fibrosis. The enhanced therapeutic potential of the modified MFG-E8 was demonstrated in various liver fibrosis animal models, and the efficacy was further confirmed in human hepatic stellate cells and a liver spheroid model. In the subsequent analysis, we found that the modified MFG-E8 more efficiently suppressed transforming growth factor β (TGF-β) signaling than the original form of MFG-E8, and it deactivated the proliferation of hepatic stellate cells in the liver disease environment through interfering with the interactions between integrins (αvβ3 & αvβ5) and TGF-βRI. Furthermore, the protein preferentially delivered in the liver after administration, and the safety profiles of the protein were demonstrated in male and female rat models. Therefore, in conclusion, this modified MFG-E8 provides a promising new therapeutic strategy for treating fibrotic diseases.
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Affiliation(s)
- Geun Ho An
- Department of New Drug Development, NEXEL Co., Ltd., 8th Floor, 55 Magokdong-ro, Gangseo-gu, Seoul 07802, Korea; (G.H.A.); (J.L.); (J.C.); (J.-C.K.); (J.-H.P.); (M.K.); (C.H.)
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Science Campus, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Korea
| | - Jaehun Lee
- Department of New Drug Development, NEXEL Co., Ltd., 8th Floor, 55 Magokdong-ro, Gangseo-gu, Seoul 07802, Korea; (G.H.A.); (J.L.); (J.C.); (J.-C.K.); (J.-H.P.); (M.K.); (C.H.)
| | - Xiong Jin
- School of Pharmacy, Henan University, Jin Ming Ave, Kaifeng 475004, China;
| | - Jinwoo Chung
- Department of New Drug Development, NEXEL Co., Ltd., 8th Floor, 55 Magokdong-ro, Gangseo-gu, Seoul 07802, Korea; (G.H.A.); (J.L.); (J.C.); (J.-C.K.); (J.-H.P.); (M.K.); (C.H.)
| | - Joon-Chul Kim
- Department of New Drug Development, NEXEL Co., Ltd., 8th Floor, 55 Magokdong-ro, Gangseo-gu, Seoul 07802, Korea; (G.H.A.); (J.L.); (J.C.); (J.-C.K.); (J.-H.P.); (M.K.); (C.H.)
| | - Jung-Hyuck Park
- Department of New Drug Development, NEXEL Co., Ltd., 8th Floor, 55 Magokdong-ro, Gangseo-gu, Seoul 07802, Korea; (G.H.A.); (J.L.); (J.C.); (J.-C.K.); (J.-H.P.); (M.K.); (C.H.)
| | - Minkyung Kim
- Department of New Drug Development, NEXEL Co., Ltd., 8th Floor, 55 Magokdong-ro, Gangseo-gu, Seoul 07802, Korea; (G.H.A.); (J.L.); (J.C.); (J.-C.K.); (J.-H.P.); (M.K.); (C.H.)
| | - Choongseong Han
- Department of New Drug Development, NEXEL Co., Ltd., 8th Floor, 55 Magokdong-ro, Gangseo-gu, Seoul 07802, Korea; (G.H.A.); (J.L.); (J.C.); (J.-C.K.); (J.-H.P.); (M.K.); (C.H.)
| | - Jong-Hoon Kim
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Science Campus, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Korea
- Correspondence: (J.-H.K.); (D.-H.W.)
| | - Dong-Hun Woo
- Department of New Drug Development, NEXEL Co., Ltd., 8th Floor, 55 Magokdong-ro, Gangseo-gu, Seoul 07802, Korea; (G.H.A.); (J.L.); (J.C.); (J.-C.K.); (J.-H.P.); (M.K.); (C.H.)
- Correspondence: (J.-H.K.); (D.-H.W.)
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Liver Cirrhosis, Etiology and Clinical Characteristics Disparities Among Minority Population. J Immigr Minor Health 2021; 24:1122-1128. [PMID: 34453643 DOI: 10.1007/s10903-021-01263-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/18/2021] [Indexed: 10/20/2022]
Abstract
Liver cirrhosis (LC) is a common disease with varied primary causes and ethnic disparities. Clinical characteristics and outcomes of Arab Bedouin (AB) and Jewish patients with LC were retrospective collected and compared. We included 1048 patients, 95 (9%) Arab Bedouin and 953 (91%) Jewish patients. The incidence of cirrhosis was much lower among AB. Age at diagnosis was 47 ± 18 years among Bedouins compared to 61 ± 13 years (p < 0.001) among Jews. The most frequent causes of cirrhosis among Bedouin patients were fatty liver 21.1%, cryptogenic 20%, hepatitis B 17.9% and autoimmune hepatitis 15.8%, while hepatitis C (39.2%), fatty liver (17.2%) and alcoholic liver disease (14.4%) were most common among Jewish patients. An all-cause mortality of 48.4% was observed in AB patients compared to 66.4% in Jewish patients (p < 0.001). Significant disparities regarding incidence, clinical characteristics and outcomes of cirrhosis among Arab Bedouin compared with Jewish population were found.
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Bonacini M, Kassamali F, Kari S, Lopez Barrera N, Kohla M. Racial differences in prevalence and severity of non-alcoholic fatty liver disease. World J Hepatol 2021; 13:763-773. [PMID: 34367497 PMCID: PMC8326166 DOI: 10.4254/wjh.v13.i7.763] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 04/08/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
The aim of this review is to assess the evidence regarding racial differences in the prevalence and severity of nonalcoholic fatty liver disease (NAFLD). We reviewed the published literature that reported prevalence, severity, and genetic associations of NAFLD in different ethnic groups. The metabolic syndrome (MetS) has been associated with NAFLD, but each component of the MetS is present in various races in different percentages and their effect on NAFLD appears to be dissimilar. An elevated triglyceride (TG) level seems to have the strongest association with NAFLD. The latter is more prevalent in Hispanic patients; Blacks have lower TG levels and a lower NAFLD prevalence, compared to Caucasians or Hispanics. The severity of liver fibrosis is lower in some, but not all biopsy-based studies of Black patients. No study has evaluated the severity of liver disease controlling for the individual components of MetS, especially TG. Important racial differences in the prevalence of selected genetic polymorphisms, particularly PNPLA-3 and MBOAT7 have been documented, together with their effects on the prevalence of liver steatosis and fibrosis. Data on overall and liver mortality have found no significant differences according to race/ethnicity, with the possible exception of one paper reporting lower cirrhosis mortality in Black patients. We conclude that NAFLD is more prevalent in Hispanics and less in Blacks. This is supported by differences in key genetic polymorphisms associated with hepatic fat storage. However, there is presently insufficient evidence to firmly conclude that race, per se, plays a role in the development of liver fibrosis and its complications. Further studies, appropriately controlled for diet, exercise, and individual MetS parameters are needed.
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Affiliation(s)
- Maurizio Bonacini
- Department of Gastroenterology and Hepatology, California Pacific Medical Center, California Pacific Medical Center, San Francisco, CA 94115, United States.
| | - Farah Kassamali
- Department of Gastroenterology and Hepatology, California Pacific Medical Center, San Francisco, CA 94115, United States
| | - Swathi Kari
- Department of Internal Medicine, St. Mary's medical Center, San Francisco, CA 94117, United States
| | | | - Mohamed Kohla
- Department of Hepatology, National Liver Institute, Menoufiya University, Shibin Al Kom 32511, Menoufiya, Egypt
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Sun W, Liu P, Yang B, Wang M, Wang T, Sun W, Wang X, Zheng W, Song X, Li J. A network pharmacology approach: Inhibition of the NF-κB signaling pathway contributes to the NASH preventative effect of an Oroxylum indicum seed extract in oleic acid-stimulated HepG2 cells and high-fat diet-fed rats. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 88:153498. [PMID: 33640247 DOI: 10.1016/j.phymed.2021.153498] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 01/05/2021] [Accepted: 02/05/2021] [Indexed: 06/12/2023]
Abstract
BACKGROUND The incidence of nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH), has significantly increased in recent years and has become an important public health issue. However, no U.S. Food and Drug Administration (FDA)-approved first-line drug is currently available for the treatment of NAFLD and NASH; therefore, research on new drugs is currently a hot topic. Oroxylum indicum (Linn.) Kurz is extensively distributed in South China and South Asia and has many biological activities. However, its effects on NAFLD or even NASH and the corresponding mechanisms are still not clear. PURPOSE To investigate the effect and mechanism of O. indicum seed extract (OISE) on preventing anti-inflammatory action in the progression from simple nonalcoholic fatty liver (NAFL) to NASH. METHODS A network pharmacology method to construct ingredient-target networks and the protein-protein interaction (PPI) network of OISE in NASH were constructed for topological analyses and hub-target screening. Enrichment analyses were performed to identify the critical biological processes and signaling pathways. Simultaneously, in vitro and in vivo experiments investigated the effect and mechanism of OISE, baicalein, and chrysin on inflammation by biochemical indicator detection, luciferase reporters, pathological staining, and immunoblotting in oleic acid-stimulated HepG2 cells or in high-fat diet-fed rats. RESULTS The network pharmacology showed that OISE prevented the development and progression of NAFL into NASH through various pathways and targets and that the nuclear factor NF-κB (NF-κB) pathway regulated by baicalein and chrysin played an important role in the treatment of NASH. In in vitro experiments, we further showed that OISE and its ingredients, namely, baicalein and chrysin, all improved the inflammatory status in oleic acid-stimulated HepG2 cells, inhibited the nuclear transcriptional activities of NF-κB, increased the IκB level, and decreased the phosphorylation level of NF-κB. Furthermore, in a high-fat diet-induced NASH model in rats, we also showed that OISE prevented the development and progression of NASH by inhibiting the nuclear transcriptional activity of NF-κB. CONCLUSION OISE suppressed inflammatory responses and prevented the development and progression of NAFL into NASH through inhibition of the nuclear transcriptional activity of NF-κB. OISE may be used to treat NAFLD through many functions, including an increase in insulin sensitivity, a decrease in lipid accumulation in the liver, suppression of inflammation, and clearance of free radicals.
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Affiliation(s)
- Wenlong Sun
- Institute of Biomedical Research, School of Life Sciences, Shandong University of Technology, Zibo, Shandong 255000, China.
| | - Panpan Liu
- Institute of Biomedical Research, School of Life Sciences, Shandong University of Technology, Zibo, Shandong 255000, China
| | - Bendong Yang
- Institute of Biomedical Research, School of Life Sciences, Shandong University of Technology, Zibo, Shandong 255000, China
| | - Meng Wang
- Institute of Biomedical Research, School of Life Sciences, Shandong University of Technology, Zibo, Shandong 255000, China
| | - Tianqi Wang
- College of Agriculture, Yangtze University, Jingzhou, Hubei 434000, China
| | - Wenbo Sun
- School of Resources and Environmental Engineering, Shandong University of Technology, Zibo, Shandong 255000, China
| | - Xudong Wang
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, Zhejiang 310000, China
| | - Weilong Zheng
- Institute of Biomass Resources, Taizhou University, Taizhou, Zhejiang 317700, China
| | - Xinhua Song
- Institute of Biomedical Research, School of Life Sciences, Shandong University of Technology, Zibo, Shandong 255000, China.
| | - Jingda Li
- College of Life Science, Yangtze University, Jingzhou, Hubei 434000, China.
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Fan S, Shi X, Yao J, Zhong M, Feng P. The efficacy of glucagon-like peptide 1 receptor agonists in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis of randomized controlled trials. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2021; 112:627-635. [PMID: 32496108 DOI: 10.17235/reed.2020.6392/2019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND non-alcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of metabolic syndrome and is highly prevalent all over the world. New drugs are urgently needed for the treatment of NAFLD. The aim of this meta-analysis was to assess the efficacy of glucagon-like peptide 1 receptor agonists (GLP-1RAs) in patients with NAFLD. METHOD English language publications in the PubMed, Cochrane Library, Embase and Web of Science databases were searched from inception to October 2019. All randomized controlled trials (RCTs) of GLP-1RAs treatment for NAFLD were considered. Standardized mean difference (SMD) with 95 % confidence intervals (CIs) were pooled using the fixed-effects or random-effects model. RESULTS six RCTs, involving 406 patients, were included in the analysis. A significant improvement was found in liver fat fraction (LFF) (SMD = -0.33, 95 % CI, -0.64 to -0.03, p = 0.034), body mass index (BMI) (SMD: -0.89, 95 % CI: -1.60 to -0.19, p = 0.012) and adiponectin (SMD: 0.66, 95 % CI: 0.37 to 0.95, p = 0.000) with GLP-1RAs treatment. There were no significant differences in serum alanine aminotransferase (ALT) (SMD: -0.52, 95 % CI: -1.04 to 0.01, p = 0.054) and aspartate transaminase (AST) (SMD: -0.20, 95 % CI: -0.54 to 0.15, p = 0.134) reduction between the GLP-1RAs and control groups. In the subgroup analysis, exenatide was associated with an improvement in serum ALT (SMD = -1.25, 95 % CI: -1.68 to -0.82, p = 0.000) and AST (SMD = -0.62, 95 % CI: -1.16 to -0.08, p = 0.024). Liraglutide was associated with a reduction in BMI (SMD = -0.44, 95 % CI: -0.77 to -0.11, p = 0.010) and an increase in adiponectin (SMD = -0.33, 95 % CI, -0.64 to -0.03, p = 0.034). CONCLUSION our study suggested that GLP-1RAs may improve LFF, BMI and adiponectin in patients with NAFLD. Furthermore, the potential efficacy to treat NAFLD was also shown. More high-quality RCTs are needed to validate our findings.
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Affiliation(s)
- Simin Fan
- Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, China
| | - Xiaoyan Shi
- Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, China
| | - Jia Yao
- Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, China
| | - Min Zhong
- Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, China
| | - Peimin Feng
- Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, China
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Mu J, Tan F, Zhou X, Zhao X. Lactobacillus fermentum CQPC06 in naturally fermented pickles prevents non-alcoholic fatty liver disease by stabilizing the gut-liver axis in mice. Food Funct 2021; 11:8707-8723. [PMID: 32945305 DOI: 10.1039/d0fo01823f] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Herein, we used a HFD/F to induce NAFLD in mice and intervened with CQPC06 to determine the preventive effect of CQPC06 on NAFLD and its potential regulatory mechanism. C57BL/6J mice were fed with LFD, HFD/F, HFD/F supplemented with CQPC06, and HFD/F supplemented with LDBS for 8 weeks to test the properties of the probiotic. Biochemical and molecular biology methods were used to determine the levels of related indexes in mouse serum, liver tissue, epididymal fat, small intestine tissue, and feces. The results showed that CQPC06 exhibited satisfactory probiotic properties, significantly inhibited mouse weight gain, and decreased the liver index and serum lipid levels, including ALT, AKP, AST, TC, TG, LDL-C, LPS, and HDL-C levels. The HOMA-IR index calculated based on the blood glucose levels and serum insulin levels showed that the HOMA-IR index of NAFLD mice treated with CQPC06 significantly decreased. From the molecular biology level, CQPC06 significantly increased the mRNA and protein expression of PPAR-α, CYP7A1, CPT1, and LPL in NAFLD mouse livers, and decreased the expression of PPAR-γ and C/EBP-α. Furthermore, CQPC06 enhanced the expression of ZO-1, occludin, and claudin-1 in the small intestine of NAFLD mice, and decreased the expression of CD36. CQPC06 decreased the level of Firmicutes and increased the levels of Bacteroides and Akkermansia in the feces of NAFLD mice, and the ratio of Firmicutes/Bacteroides was significantly decreased. CQPC06 is highly resistant in vitro and survived in the gastrointestinal tract and exerted its probiotic effect, altered the intestinal microecology of NAFLD mice, and played an important role in NAFLD prevention through the unique anatomical advantages of the gut-liver axis. There was a clear preventive effect with high concentrations of CQPC06 and it was stronger than that of l-carnitine.
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Affiliation(s)
- Jianfei Mu
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing 400067, China. and Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing 400067, China and Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing 400067, China and College of Food Science, Southwest University, Chongqing 400715, China
| | - Fang Tan
- Department of Public Health, Our Lady of Fatima University, Valenzuela 838, Philippines
| | - Xianrong Zhou
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing 400067, China. and Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing 400067, China and 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. and Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing 400067, China and Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing 400067, China
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Iron depletion attenuates steatosis in a mouse model of non-alcoholic fatty liver disease: Role of iron-dependent pathways. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166142. [PMID: 33839281 DOI: 10.1016/j.bbadis.2021.166142] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 03/23/2021] [Accepted: 04/01/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Iron has been proposed as influencing the progression of liver disease in subjects with non-alcoholic fatty liver disease (NAFLD). We have previously shown that, in the Hfe-/- mouse model of hemochromatosis, feeding of a high-calorie diet (HCD) leads to increased liver injury. In this study we investigated whether the feeding of an iron deficient/HCD to Hfe-/- mice influenced the development of NAFLD. METHODS Liver histology was assessed in Hfe-/- mice fed a standard iron-containing or iron-deficient diet plus or minus a HCD. Hepatic iron concentration, serum transferrin saturation and free fatty acid were measured. Expression of genes implicated in iron regulation and fatty liver disease was determined by quantitative real-time PCR (qRT-PCR). RESULTS Standard iron/HCD-fed mice developed severe steatosis whereas NAS score was reduced in mice fed iron-deficient HCD. Mice fed iron-deficient HCD had lower liver weights, lower transferrin saturation and decreased ferroportin and hepcidin gene expression than HCD-fed mice. Serum non-esterified fatty acids were increased in iron-deficient HCD-fed mice compared with standard iron HCD. Expression analysis indicated that genes involved in fatty-acid binding and mTOR pathways were regulated by iron depletion. CONCLUSIONS Our results indicate that decreasing iron intake attenuates the development of steatosis resulting from a high calorie diet. These results also suggest that human studies of agents that modify iron balance in patients with NAFLD should be revisited.
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Cai C, Chen DZ, Tu HX, Chen WK, Ge LC, Fu TT, Tao Y, Ye SS, Li J, Lin Z, Wang XD, Xu LM, Chen YP. MicroRNA-29c Acting on FOS Plays a Significant Role in Nonalcoholic Steatohepatitis Through the Interleukin-17 Signaling Pathway. Front Physiol 2021; 12:597449. [PMID: 33927635 PMCID: PMC8078210 DOI: 10.3389/fphys.2021.597449] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 03/04/2021] [Indexed: 12/13/2022] Open
Abstract
Nonalcoholic fatty liver disease is the most common hepatic disease in western countries and is even more ubiquitous in Asian countries. Our study determined that TH17/Treg cells were imbalanced in animal models. Based on our interest in the mechanism underlying TH17/Treg cell imbalance in nonalcoholic fatty liver mice, we conducted a joint bioinformatics analysis to further investigate this process. Common gene sequencing analysis was based on one trial from one sequencing platform, where gene expression analysis and enrichment analysis were the only analyses performed. We compared different sequencing results from different trials performed using different sequencing platforms, and we utilized the intersection of these analytical results to perform joint analysis. We used a bioinformatics analysis method to perform enrichment analysis and map interaction network analysis and predict potential microRNA sites. Animal experiments were also designed to validate the results of the data analysis based on quantitative polymerase chain reaction (qPCR) and western blotting. Our results revealed 8 coexisting differentially expressed genes (DEGs) and 7 hinge genes. The identified DEGs may influence nonalcoholic steatosis hepatitis through the interleukin-17 pathway. We found that microRNA-29c interacts with FOS and IGFBP1. Polymerase chain reaction analyses revealed both FOS and microRNA-29c expression in NASH mice, and western blot analyses indicated the same trend with regard to FOS protein levels. Based on these results, we suggest that microRNA-29c acts on FOS via the interleukin-17 signaling pathway to regulate TH17/Treg cells in NASH patients.
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Affiliation(s)
- Chao Cai
- Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Disease, Hepatology Institute of Wenzhou Medical University, Wenzhou, China
| | - Da-Zhi Chen
- Department of Gastroenterology, The First Hospital of Peking University, Beijing, China
| | - Han-Xiao Tu
- Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Disease, Hepatology Institute of Wenzhou Medical University, Wenzhou, China
| | - Wen-Kai Chen
- Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Disease, Hepatology Institute of Wenzhou Medical University, Wenzhou, China
| | - Li-Chao Ge
- Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Disease, Hepatology Institute of Wenzhou Medical University, Wenzhou, China
| | - Tian-Tian Fu
- School of Wenzhou Medical University, Wenzhou, China
| | - Ying Tao
- Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Disease, Hepatology Institute of Wenzhou Medical University, Wenzhou, China
| | - Sha-Sha Ye
- Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Disease, Hepatology Institute of Wenzhou Medical University, Wenzhou, China
| | - Ji Li
- Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Disease, Hepatology Institute of Wenzhou Medical University, Wenzhou, China
| | - Zhuo Lin
- Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Disease, Hepatology Institute of Wenzhou Medical University, Wenzhou, China
| | - Xiao-Dong Wang
- Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Disease, Hepatology Institute of Wenzhou Medical University, Wenzhou, China
| | - Lan-Man Xu
- Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Disease, Hepatology Institute of Wenzhou Medical University, Wenzhou, China.,Department of Infectious Diseases and Liver Diseases, Ningbo Medical Centre Lihuili Hospital, Affiliated Lihuili Hospital of Ningbo University, Ningbo Institute of Innovation for Combined Medicine and Engineering, Ningbo, China
| | - Yong-Ping Chen
- Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Disease, Hepatology Institute of Wenzhou Medical University, Wenzhou, China
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Ketogenic Diet Enhances the Cholesterol Accumulation in Liver and Augments the Severity of CCl 4 and TAA-Induced Liver Fibrosis in Mice. Int J Mol Sci 2021; 22:ijms22062934. [PMID: 33805788 PMCID: PMC7998170 DOI: 10.3390/ijms22062934] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 12/25/2022] Open
Abstract
Persistent chronic liver diseases increase the scar formation and extracellular matrix accumulation that further progress to liver fibrosis and cirrhosis. Nevertheless, there is no antifibrotic therapy to date. The ketogenic diet is composed of high fat, moderate to low-protein, and very low carbohydrate content. It is mainly used in epilepsy and Alzheimer’s disease. However, the effects of the ketogenic diet on liver fibrosis remains unknown. Through ketogenic diet consumption, β-hydroxybutyrate (bHB) and acetoacetate (AcAc) are two ketone bodies that are mainly produced in the liver. It is reported that bHB and AcAc treatment decreases cancer cell proliferation and promotes apoptosis. However, the influence of bHB and AcAc in hepatic stellate cell (HSC) activation and liver fibrosis are still unclear. Therefore, this study aimed to investigate the effect of the ketogenic diet and ketone bodies in affecting liver fibrosis progression. Our study revealed that feeding a high-fat ketogenic diet increased cholesterol accumulation in the liver, which further enhanced the carbon tetrachloride (CCl4)- and thioacetamide (TAA)-induced liver fibrosis. In addition, more severe liver inflammation and the loss of hepatic antioxidant and detoxification ability were also found in ketogenic diet-fed fibrotic mouse groups. However, the treatment with ketone bodies (bHB and AcAc) did not suppress transforming growth factor-β (TGF-β)-induced HSC activation, platelet-derived growth factor (PDGF)-BB-triggered proliferation, and the severity of CCl4-induced liver fibrosis in mice. In conclusion, our study demonstrated that feeding a high-fat ketogenic diet may trigger severe steatohepatitis and thereby promote liver fibrosis progression. Since a different ketogenic diet composition may exert different metabolic effects, more evidence is necessary to clarify the effects of a ketogenic diet on disease treatment.
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Lopez-Lopez V, Ruiz-Manzanera JJ, Eshmuminov D, Lehmann K, Schneider M, von der Groeben M, de Angulo DR, Gajownik U, Pons JA, Sánchez-Bueno F, Robles-Campos R, Ramírez-Romero P. Are We Ready for Bariatric Surgery in a Liver Transplant Program? A Meta-Analysis. Obes Surg 2021; 31:1214-1222. [PMID: 33225408 DOI: 10.1007/s11695-020-05118-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 10/30/2020] [Accepted: 11/10/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND Obesity-related non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are two main causes of end-stage liver disease requiring a liver transplantation. Studies exploring bariatric surgery in the liver transplantation setting have increased in recent years; however, a systematic analysis of the topic is lacking to date. This meta-analysis was conducted to explore the perioperative and long-term outcomes of bariatric surgery in obese patients undergoing liver transplantation. METHODS Electronic databases were systematically searched for studies reporting bariatric surgery in patients undergoing liver transplantation. The primary outcomes were postoperative complications and mortality. We also extracted data about excess weight loss, body mass index, and improvement of comorbidities after bariatric surgery. RESULTS A total of 96 patients from 8 articles were included. Bariatric surgery-related morbidity and mortality rates were 37% (95% CI 0.27-0.47) and 0.6% (95% CI 0.02-0.13), respectively. Body mass index at 24 months was 31.02 (95% CI 25.96-36.09) with a percentage excess weight loss at 12 and 24 months of 44.08 (95% CI 27.90-60.26) and 49.2 (95% CI 31.89-66.66), respectively. After bariatric surgery, rates of improvement of arterial hypertension and diabetes mellitus were 61% (95% CI 0.45-0.75) and 45% (95% CI 0.25-0.66), respectively. In most patients, bariatric surgery was performed after liver transplant and the most frequent technique was sleeve gastrectomy. CONCLUSIONS Bariatric surgery can be performed safely in the setting of liver transplantation resulting in improvement of obesity-related comorbidities. The optimal timing and technique require further studies.
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Affiliation(s)
- Víctor Lopez-Lopez
- Department of General, Visceral and Transplantation Surgery, Clinic and University Hospital Virgen de la Arrixaca, IMIB-ARRIXACA, Murcia, Spain.
| | - Juan José Ruiz-Manzanera
- Department of General, Visceral and Transplantation Surgery, Clinic and University Hospital Virgen de la Arrixaca, IMIB-ARRIXACA, Murcia, Spain
| | - Dilmurodjon Eshmuminov
- Department of Surgery and Transplantation, Swiss Hepato-Pancreato-Biliary (HPB) Center, University Hospital Zurich, Zurich, Switzerland
| | - Kuno Lehmann
- Department of Surgery and Transplantation, Swiss Hepato-Pancreato-Biliary (HPB) Center, University Hospital Zurich, Zurich, Switzerland
| | - Marcel Schneider
- Department of Surgery and Transplantation, Swiss Hepato-Pancreato-Biliary (HPB) Center, University Hospital Zurich, Zurich, Switzerland
| | | | - David Ruiz de Angulo
- Department of General, Visceral and Transplantation Surgery, Clinic and University Hospital Virgen de la Arrixaca, IMIB-ARRIXACA, Murcia, Spain
| | - Ursula Gajownik
- Department of Hepatology, Clinic and University Hospital Virgen de la Arrixaca, IMIB-ARRIXACA, Murcia, Spain
| | - Jose Antonio Pons
- Department of Hepatology, Clinic and University Hospital Virgen de la Arrixaca, IMIB-ARRIXACA, Murcia, Spain
| | - Francisco Sánchez-Bueno
- Department of General, Visceral and Transplantation Surgery, Clinic and University Hospital Virgen de la Arrixaca, IMIB-ARRIXACA, Murcia, Spain
| | - Ricardo Robles-Campos
- Department of General, Visceral and Transplantation Surgery, Clinic and University Hospital Virgen de la Arrixaca, IMIB-ARRIXACA, Murcia, Spain
| | - Pablo Ramírez-Romero
- Department of General, Visceral and Transplantation Surgery, Clinic and University Hospital Virgen de la Arrixaca, IMIB-ARRIXACA, Murcia, Spain
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Xie X, Feng Y, Lyu Z, Wang L, Yang Y, Bai Y, Liu C, Wu H, Ren W, Zhu Q. Liver stiffness as measured by two-dimensional shear wave elastography overestimates the stage of fibrosis in patients with chronic hepatitis B and hepatic steatosis. Clin Res Hepatol Gastroenterol 2021; 45:101421. [PMID: 32312597 DOI: 10.1016/j.clinre.2020.03.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 02/25/2020] [Accepted: 03/23/2020] [Indexed: 02/07/2023]
Abstract
Two-dimensional shear wave elastography (2D-SWE) is a non-invasive technique for measuring liver stiffness (LS) and is used to assess the degree of hepatic fibrosis in patients with chronic hepatitis B (CHB). Despite its usefulness, several factors, other than hepatic fibrosis, can affect its diagnostic accuracy. Hepatic steatosis (HS) is a common lesion in CHB that has increasingly been getting attention in the field of disease development; however, its influence on the measurement of LS remains unclear. We aimed to determine whether HS affects the diagnostic accuracy of 2D-SWE in patients with CHB. Serum parameters and LS values were obtained from 161 patients with CHB. The degrees of hepatic fibrosis and inflammatory activity were estimated based on the METAVIR Cooperative Study Group criteria, and the extent of HS was defined as the percentage of hepatocytes containing fat droplets using oil red staining. We found that LS values were independently correlated with HS in the early stages of hepatic fibrosis (F0-F2 or F0-3). Furthermore, LS values in patients with significant steatosis (S≥10%) were higher than the counterpart in fibrosis stages F0-2 (6.82±1.57 vs. 7.92±1.99; p=0.010) and F0-3 (7.18±1.84 vs. 8.25±1.91; p=0.007). Therefore, false positive rates (FPRs) in the diagnosis of advanced fibrosis (16.00% vs. 37.04%, p=0.037) and cirrhosis (6.67% vs. 21.62%, p=0.030) were higher in patients with significant steatosis. In conclusion, the use of 2D-SWE in the measurement of LS overestimates the stage of hepatic fibrosis in CHB patients with HS>10%. This should be taken into consideration to combine LS results with other non-invasive parameters to improve its accuracy.
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Affiliation(s)
- Xiaoyu Xie
- Department of Gastroenterology, Shangdong Provincial Hospital Affiliated to Shandong University, 324, Jing 5 Rd, Jinan, 250021, Shandong Province, China
| | - Yuemin Feng
- Department of Gastroenterology, Shangdong Provincial Hospital Affiliated to Shandong University, 324, Jing 5 Rd, Jinan, 250021, Shandong Province, China
| | - Zhuozhen Lyu
- Department of Infectious Disease, Shangdong Provincial Hospital Affiliated to Shandong University, 324, Jing 5 Rd, Jinan, 250021, Shandong Province, China
| | - Le Wang
- Department of Geriatrics, Department of Geriatric, Gastroenterology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China
| | - Yao Yang
- Department of Gastroenterology, Shangdong Provincial Hospital Affiliated to Shandong University, 324, Jing 5 Rd, Jinan, 250021, Shandong Province, China
| | - Yuping Bai
- Department of Gastroenterology, Shangdong Provincial Hospital Affiliated to Shandong University, 324, Jing 5 Rd, Jinan, 250021, Shandong Province, China
| | - Chenxi Liu
- Department of Gastroenterology, Shangdong Provincial Hospital Affiliated to Shandong University, 324, Jing 5 Rd, Jinan, 250021, Shandong Province, China
| | - Hao Wu
- Department of Gastroenterology, Shangdong Provincial Hospital Affiliated to Shandong University, 324, Jing 5 Rd, Jinan, 250021, Shandong Province, China
| | - Wanhua Ren
- Department of Infectious Disease, Shangdong Provincial Hospital Affiliated to Shandong University, 324, Jing 5 Rd, Jinan, 250021, Shandong Province, China.
| | - Qiang Zhu
- Department of Gastroenterology, Shangdong Provincial Hospital Affiliated to Shandong University, 324, Jing 5 Rd, Jinan, 250021, Shandong Province, China.
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Nakade Y, Kitano R, Sakamoto K, Kimoto S, Yamauchi T, Inoue T, Kobayashi Y, Ohashi T, Sumida Y, Ito K, Yoneda M. Characteristics of bile acid composition in high fat diet-induced nonalcoholic fatty liver disease in obese diabetic rats. PLoS One 2021; 16:e0247303. [PMID: 33626072 PMCID: PMC7904175 DOI: 10.1371/journal.pone.0247303] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 02/04/2021] [Indexed: 01/12/2023] Open
Abstract
Bile acid has attracted attention as a signal transmission molecule in energy metabolism. Although a high-fat diet (HFD) or obesity is known to increase hepatic fat content and alter bile acid composition, the changes in bile acid composition due to HFD or obesity remain to be elucidated. We sought to examine the bile acid composition in high fat diet-induced non-alcoholic fatty liver disease (NAFLD) in obese diabetic rats. Eight-week-old male spontaneously diabetic Torii fatty (SDTF) rats or control rats were fed an HFD. Twelve weeks post the commencement of HFD, serum and hepatic bile acid compositions and serum GLP-1 levels, which is stimulated by the secondary bile acid deoxycholic acid (DCA), were measured. The correlation between the bile acid composition and serum GLP-1 levels was also examined. While serum and hepatic levels of cholic acid (CA), a primary bile acid, tended to decrease in HFD-fed control rats, they were significantly decreased in HFD-fed SDTF rats. Hepatic CYP8B1, which plays a role in CA synthesis, the mRNA levels were significantly decreased in HFD-fed control and SDTF rats. In contrast, while serum and hepatic DCA levels were not changed in HFD-fed control rats, they were decreased in HFD-fed SDTF rats. Hepatic DCA/CA did not change in HFD-fed SDTF rats, but significantly increased in HFD-fed control rats. While serum GLP-1 levels were not changed in SDTF rats, they were significantly increased in HFD-fed control rats. Hepatic DCA/CA tended to correlate with serum GLP-1 levels, which tended to negatively correlate with the hepatic triglyceride content in SDTF rats. These results indicate that relatively increased DCA might contribute to an increase in serum GLP-1 levels, which inhibits hepatic steatosis in NAFLD.
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Affiliation(s)
- Yukiomi Nakade
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Rena Kitano
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Kazumasa Sakamoto
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Satoshi Kimoto
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Taeko Yamauchi
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Tadahisa Inoue
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Yuji Kobayashi
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Tomohiko Ohashi
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Yoshio Sumida
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Kiyoaki Ito
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Masashi Yoneda
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Aichi Medical University, Nagakute, Aichi, Japan
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47
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Dedov II, Shestakova MV, Melnichenko GA, Mazurina NV, Andreeva EN, Bondarenko IZ, Gusova ZR, Dzgoeva FK, Eliseev MS, Ershova EV, Zhuravleva MV, Zakharchuk TA, Isakov VA, Klepikova MV, Komshilova KA, Krysanova VS, Nedogoda SV, Novikova AM, Ostroumova OD, Pereverzev AP, Rozhivanov RV, Romantsova TI, Ruyatkina LA, Salasyuk AS, Sasunova AN, Smetanina SA, Starodubova AV, Suplotova LA, Tkacheva ON, Troshina EA, Khamoshina MV, Chechelnitskaya SM, Shestakova EA, Sheremet’eva EV. INTERDISCIPLINARY CLINICAL PRACTICE GUIDELINES "MANAGEMENT OF OBESITY AND ITS COMORBIDITIES". OBESITY AND METABOLISM 2021; 18:5-99. [DOI: 10.14341/omet12714] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Affiliation(s)
| | | | | | | | | | | | | | | | - M. S. Eliseev
- Research Institute of Rheumatogy named after V.A. Nasonova
| | | | | | | | - V. A. Isakov
- Federal Research Center of Nutrition, Biotechnology and Food Safety
| | - M. V. Klepikova
- Russian Medical Academy of Continuous Professional Education
| | | | | | | | - A. M. Novikova
- Research Institute of Rheumatogy named after V.A. Nasonova
| | - O. D. Ostroumova
- A.I. Yevdokimov Moscow State University of Medicine and Dentistry
| | - A. P. Pereverzev
- Russian National Research Medical University named after N.I. Pirogov
| | | | | | | | | | - A. N. Sasunova
- Federal Research Center of Nutrition, Biotechnology and Food Safety
| | | | | | | | - O. N. Tkacheva
- Russian National Research Medical University named after N.I. Pirogov
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48
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Hernandez Roman J, Siddiqui MS. The role of noninvasive biomarkers in diagnosis and risk stratification in nonalcoholic fatty liver disease. Endocrinol Diabetes Metab 2020; 3:e00127. [PMID: 33102796 PMCID: PMC7576290 DOI: 10.1002/edm2.127] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 02/28/2020] [Accepted: 02/29/2020] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronically elevated liver enzymes. Diagnosis and risk stratification of NAFLD remains clinically challenge as patients with NAFLD are either asymptomatic or have nonspecific presenting complaints and may have normal liver enzymes. Nonalcoholic steatohepatitis (NASH), the clinically aggressive variant of NAFLD, is also difficult to differentiate noninvasively, and a liver biopsy is required to definitively diagnose NASH. Thus, the definitive diagnosis and risk stratification of NAFLD is embedded in histological assessment of the liver. Several clinical aides been investigated in an attempt to risk stratify and identify patients noninvasively as doing a liver biopsy in all patients with NAFLD are not feasible. Since these biomarkers are unable to differentiate NASH from non-NASH, they have leveraged biochemical changes within the liver as patients progress to varying degree of hepatic fibrosis to identify patients with moderate fibrosis (fibrosis stage 2 or greater) and advanced fibrosis (fibrosis stage 3 or greater) to help guide the need for additional and more definitive workup. These clinical aides span from by-products of apoptosis to statistical modelling of clinically available data to identify 'at-risk' patients with NAFLD. The current review will focus the diagnostic performance of these noninvasive serum-based biomarkers in NAFLD.
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Affiliation(s)
| | - Mohammad S. Siddiqui
- Division of Gastroenterology, Hepatology and NutritionDepartment of Internal MedicineVirginia Commonwealth University (VCU)RichmondVirginia
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49
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Ip S, Bhanji RA, Ebadi M, Mason AL, Montano-Loza AJ. De novo and recurrent liver disease. Best Pract Res Clin Gastroenterol 2020; 46-47:101688. [PMID: 33158472 DOI: 10.1016/j.bpg.2020.101688] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 09/03/2020] [Accepted: 09/18/2020] [Indexed: 01/31/2023]
Abstract
Decompensated cirrhosis due to nonalcoholic steatohepatitis (NASH), and autoimmune liver diseases (AILD) are the most common indications for liver transplantation (LT). AILD include autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). NASH and AILD share some peculiarities as they can recur in the new graft, compromising the quality of life, and graft and patient survival. De novo NASH or AIH connotes the development of these liver diseases in patients transplanted for other indications. The diagnosis of recurrent or de novo liver disease usually requires a liver biopsy aside from recurrent PSC, which can be diagnosed with compatible imaging studies and exclusion of other causes of biliary strictures. The treatment of recurrent NASH is lifestyle modifications aiming for weight loss. Recurrent and de novo AIH is usually treated with corticosteroids with or without azathioprine. Recurrent PBC should be treated with ursodeoxycholic acid. There are no proven treatment options for recurrent PSC. Patients with graft failure should be considered for repeat LT. Future investigations should use standardized diagnostic criteria for each disease, seek diagnostic biomarkers, and evaluate treatments that improve outcomes.
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Affiliation(s)
- Stephen Ip
- From the Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada.
| | - Rahima A Bhanji
- From the Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada.
| | - Maryam Ebadi
- From the Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada.
| | - Andrew L Mason
- From the Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada.
| | - Aldo J Montano-Loza
- From the Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada.
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50
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Wang Y, Wang H, Deng P, Tao T, Liu H, Wu S, Chen W, Qin J. Modeling Human Nonalcoholic Fatty Liver Disease (NAFLD) with an Organoids-on-a-Chip System. ACS Biomater Sci Eng 2020; 6:5734-5743. [DOI: 10.1021/acsbiomaterials.0c00682] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Yaqing Wang
- School of Chemistry, Dalian University of Technology, Dalian 116024, China
- Division of Biotechnology, CAS Key Laboratory of SSAC, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Hui Wang
- Division of Biotechnology, CAS Key Laboratory of SSAC, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Pengwei Deng
- Division of Biotechnology, CAS Key Laboratory of SSAC, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Tingting Tao
- Division of Biotechnology, CAS Key Laboratory of SSAC, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Haitao Liu
- Division of Biotechnology, CAS Key Laboratory of SSAC, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Shuo Wu
- School of Chemistry, Dalian University of Technology, Dalian 116024, China
| | - Wenwen Chen
- Division of Biotechnology, CAS Key Laboratory of SSAC, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jianhua Qin
- Division of Biotechnology, CAS Key Laboratory of SSAC, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100049, China
- CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
- University of Chinese Academy of Sciences, Beijing, China
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