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Ye RQ, Chen YF, Ma C, Cheng X, Guo W, Li S. Advances in identifying risk factors of metabolic dysfunction-associated alcohol-related liver disease. Biomed Pharmacother 2025; 188:118191. [PMID: 40408808 DOI: 10.1016/j.biopha.2025.118191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 05/13/2025] [Accepted: 05/21/2025] [Indexed: 05/25/2025] Open
Abstract
Metabolic dysfunction-associated alcohol-related liver disease (MetALD) is an emerging clinical entity that reflects the coexistence of metabolic dysfunction and alcohol-related liver injury. Unlike classical alcoholic liver disease (ALD), MetALD patients often present with lower to moderate alcohol consumption alongside metabolic risk factors such as obesity, insulin resistance, and dyslipidemia. These factors can synergistically worsen liver injury even at lower alcohol intake levels. Alcohol abuse remains a major global health concern, with the liver being the primary target of alcohol's toxic effects. Long-term alcohol exposure, especially when compounded by metabolic dysfunction, can accelerate the progression from steatosis to inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Besides alcohol itself, various factors, including genetic predispositions, gender, type of alcoholic beverage, drinking patterns, and co-morbidities such as viral infections (HBV, HCV) modulate disease susceptibility and severity. This review summarizes current knowledge of risk factors contributing to MetALD, highlights the synergistic interactions between metabolic dysfunction and alcohol consumption, and discusses potential strategies for disease prevention and management.
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Affiliation(s)
- Rui-Qi Ye
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China; Xinhua Clinical Medical College, Shanghai Jiao Tong University, Shanghai 200135, China
| | - Yi-Fan Chen
- College of Basic Medical Sciences, Shanghai Jiao Tong University, Shanghai 200025, China
| | - Chang Ma
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xi Cheng
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Wei Guo
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China.
| | - Sha Li
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
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Paudel D, Hao F, Goand UK, Tian S, Koehle AM, Nguyen LV, Tian Y, Patterson AD, Singh V. Elevated systemic total bile acids escalate susceptibility to alcohol-associated liver disease. iScience 2024; 27:110940. [PMID: 39398234 PMCID: PMC11467679 DOI: 10.1016/j.isci.2024.110940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 06/21/2024] [Accepted: 09/10/2024] [Indexed: 10/15/2024] Open
Abstract
Excessive alcohol consumption is a major global health problem. Individuals with alcoholic liver disease often exhibit elevated serum total bile acids (TBAs). Nevertheless, the extent to which high TBA contributes to alcohol-associated liver disease (AALD) remains elusive. To investigate this, wild-type mice were categorized into normal (nTBA) and high (hTBA) TBA groups. Both groups underwent chronic-binge ethanol feeding for 4 weeks, followed by additional weekly ethanol doses. Ethanol feeding worsened AALD in both male and female mice with elevated serum TBA, characterized by liver dysfunction and steatosis. Decreased hepatic expression of genes involved in mitochondrial β-oxidation and lipid transport in ethanol-fed hTBA mice suggests that altered fatty acid metabolism contributed to AALD. Our findings, which represent the first to link high serum TBA to increased AALD susceptibility, underscore the importance of proactive serum TBA screening as a valuable tool for identifying individuals at high risk of developing AALD.
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Affiliation(s)
- Devendra Paudel
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Fuhua Hao
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Umesh K. Goand
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Sangshan Tian
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Anthony M. Koehle
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Loi V. Nguyen
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Yuan Tian
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Andrew D. Patterson
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Vishal Singh
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA
- Center for Molecular Immunology and Infectious Disease, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, USA
- One Health Microbiome Center, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, USA
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Verma N, Vinod AP, Singal AK. The pharmacological management of alcohol-related cirrhosis: what's new? Expert Opin Pharmacother 2024; 25:1923-1941. [PMID: 39360770 DOI: 10.1080/14656566.2024.2409941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 09/24/2024] [Indexed: 10/05/2024]
Abstract
INTRODUCTION Alcohol use disorder (AUD) is present in the majority of patients with alcohol-associated liver disease (ALD), which leads to about 50% of cirrhosis-related hospitalizations and over 25% of deaths worldwide. Patients with ALD often present at an advanced stage, like cirrhosis with its complications and alcohol-associated hepatitis (AH), which has high short-term mortality. Current treatments are limited, with the limited benefit of glucocorticoids only in the short-term among patients with AH, highlighting an urgent need for novel therapies. AREAS COVERED This review applies the PIRO (Predisposition, Injury, Response, Organ dysfunction) concept to ALD, understanding an ongoing process of liver damage, and opportunities to address and halt the progression. We also highlight the significance of treating AUD to improve long-term outcomes in ALD. EXPERT OPINION Personalized therapies targeting specific genetic profiles and multiple pathogenic pathways are crucial in managing ALD. Emerging therapies like gut-liver-brain axis modulators like fecal microbiota transplant and probiotics, interleukin-22, granulocyte-colony stimulating factor (G-CSF) and stem cells, epigenetic regulators of inflammation and regeneration are encouraging with the potential of efficacy in patients with ALD. Liver transplantation (LT) is a definitive therapy for advanced cirrhosis with increasing impetus on early LT select patients with active alcohol use.
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Affiliation(s)
- Nipun Verma
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashwin P Vinod
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashwani K Singal
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Louisville School of Medicine, Louisville, KY, USA
- Department of Transplant Hepatology, Jewish Hospital and Trager Transplant Center, Louisville, Kentucky, USA
- Department of Research, Veteran Affairs Medical Center, Sioux Falls, SD, USA
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Staller DW, Bennett RG, Mahato RI. Therapeutic perspectives on PDE4B inhibition in adipose tissue dysfunction and chronic liver injury. Expert Opin Ther Targets 2024; 28:545-573. [PMID: 38878273 PMCID: PMC11305103 DOI: 10.1080/14728222.2024.2369590] [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: 04/01/2024] [Accepted: 06/14/2024] [Indexed: 06/20/2024]
Abstract
INTRODUCTION Chronic liver disease (CLD) is a complex disease associated with profound dysfunction. Despite an incredible burden, the first and only pharmacotherapy for metabolic-associated steatohepatitis was only approved in March of this year, indicating a gap in the translation of preclinical studies. There is a body of preclinical work on the application of phosphodiesterase 4 inhibitors in CLD, none of these molecules have been successfully translated into clinical use. AREAS COVERED To design therapies to combat CLD, it is essential to consider the dysregulation of other tissues that contribute to its development and progression. As such, proper therapies must combat this throughout the body rather than focusing only on the liver. To detail this, literature characterizing the pathogenesis of CLD was pulled from PubMed, with a particular focus placed on the role of PDE4 in inflammation and metabolism. Then, the focus is shifted to detailing the available information on existing PDE4 inhibitors. EXPERT OPINION This review gives a brief overview of some of the pathologies of organ systems that are distinct from the liver but contribute to disease progression. The demonstrated efficacy of PDE4 inhibitors in other human inflammatory diseases should earn them further examination for the treatment of CLD.
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Affiliation(s)
- Dalton W. Staller
- Department of Cellular & Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Robert G. Bennett
- Department of Internal Medicine, Division of Diabetes Endocrinology and Metabolism, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
- VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA
| | - Ram I. Mahato
- Department of Cellular & Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA
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Tran M, Gilling S, Wu J, Wang L, Shin DJ. miR-141/200c contributes to ethanol-mediated hepatic glycogen metabolism. Mol Metab 2024; 84:101942. [PMID: 38642890 PMCID: PMC11060962 DOI: 10.1016/j.molmet.2024.101942] [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: 04/04/2024] [Accepted: 04/15/2024] [Indexed: 04/22/2024] Open
Abstract
OBJECTIVE Hepatic glucose metabolism is profoundly perturbed by excessive alcohol intake. miR-141/200c expression is significantly induced by chronic ethanol feeding. This study aimed at identifying the role of miR-141/200c in glucose homeostasis during chronic ethanol exposure. METHODS WT and miR-141/200c KO mice were fed a control or an ethanol diet for 30 days, followed by a single binge of maltose dextrin or ethanol, respectively. Untargeted metabolomics analysis of hepatic primary metabolites was performed along with analyses for liver histology, gene expression, intracellular signaling pathways, and physiological relevance. Primary hepatocytes were used for mechanistic studies. RESULTS miR-141/200c deficiency rewires hepatic glucose metabolism during chronic ethanol feeding, increasing the abundance of glucose intermediates including G6P, an allosteric activator for GS. miR-141/200c deficiency replenished glycogen depletion during chronic ethanol feeding accompanied by reduced GS phosphorylation in parallel with increased expression of PP1 glycogen targeting subunits. Moreover, miR-141/200c deficiency prevented ethanol-mediated increases in AMPK and CaMKK2 activity. Ethanol treatment reduced glycogen content in WT-hepatocytes, which was reversed by dorsomorphin, a selective AMPK inhibitor, while KO-hepatocytes displayed higher glycogen content than WT-hepatocytes in response to ethanol treatment. Furthermore, treatment of hepatocytes with A23187, a calcium ionophore activating CaMKK2, lowered glycogen content in WT-hepatocytes. Notably, the suppressive effect of A23187 on glycogen deposition was reversed by dorsomorphin, demonstrating that the glycogen depletion by A23187 is mediated by AMPK. KO-hepatocytes exhibited higher glycogen content than WT-hepatocytes in response to A23187. Finally, miR-141/200c deficiency led to improved glucose tolerance and insulin sensitivity during chronic ethanol feeding. CONCLUSIONS miR-141/200c deficiency replenishes ethanol-mediated hepatic glycogen depletion through the regulation of GS activity and calcium signaling coupled with the AMPK pathway, improving glucose homeostasis and insulin sensitivity. These results underscore miR-141/200c as a potential therapeutic target for the management of alcohol intoxication.
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Affiliation(s)
- Melanie Tran
- Department of Physiology and Neurobiology, University of Connecticut, 75 N. Eagleville Rd, Storrs, CT 06269, USA
| | - Shaynian Gilling
- Department of Physiology and Neurobiology, University of Connecticut, 75 N. Eagleville Rd, Storrs, CT 06269, USA
| | - Jianguo Wu
- Department of Physiology and Neurobiology, University of Connecticut, 75 N. Eagleville Rd, Storrs, CT 06269, USA
| | - Li Wang
- Department of Internal Medicine, Section of Digestive Diseases, Yale University, 333 Cedar St, New Haven, CT 06510, USA
| | - Dong-Ju Shin
- Department of Physiology and Neurobiology, University of Connecticut, 75 N. Eagleville Rd, Storrs, CT 06269, USA.
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Qasem B, Dąbrowska A, Króliczewski J, Łyczko J, Marycz K. Trodusquemine (MSI-1436) Restores Metabolic Flexibility and Mitochondrial Dynamics in Insulin-Resistant Equine Hepatic Progenitor Cells (HPCs). Cells 2024; 13:152. [PMID: 38247843 PMCID: PMC10814577 DOI: 10.3390/cells13020152] [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: 11/18/2023] [Revised: 12/31/2023] [Accepted: 01/12/2024] [Indexed: 01/23/2024] Open
Abstract
Equine metabolic syndrome (EMS) is a significant global health concern in veterinary medicine. There is increasing interest in utilizing molecular agents to modulate hepatocyte function for potential clinical applications. Recent studies have shown promising results in inhibiting protein tyrosine phosphatase (PTP1B) to maintain cell function in various models. In this study, we investigated the effects of the inhibitor Trodusquemine (MSI-1436) on equine hepatic progenitor cells (HPCs) under lipotoxic conditions. We examined proliferative activity, glucose uptake, and mitochondrial morphogenesis. Our study found that MSI-1436 promotes HPC entry into the cell cycle and protects them from palmitate-induced apoptosis by regulating mitochondrial dynamics and biogenesis. MSI-1436 also increases glucose uptake and protects HPCs from palmitate-induced stress by reorganizing the cells' morphological architecture. Furthermore, our findings suggest that MSI-1436 enhances 2-NBDG uptake by increasing the expression of SIRT1, which is associated with liver insulin sensitivity. It also promotes mitochondrial dynamics by modulating mitochondria quantity and morphotype as well as increasing the expression of PINK1, MFN1, and MFN2. Our study provides evidence that MSI-1436 has a positive impact on equine hepatic progenitor cells, indicating its potential therapeutic value in treating EMS and insulin dysregulation.
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Affiliation(s)
- Badr Qasem
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wrocław, Poland; (B.Q.); (A.D.); (J.K.)
| | - Agnieszka Dąbrowska
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wrocław, Poland; (B.Q.); (A.D.); (J.K.)
| | - Jarosław Króliczewski
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wrocław, Poland; (B.Q.); (A.D.); (J.K.)
| | - Jacek Łyczko
- Department of Food Chemistry and Biocatalysis, Wrocław University of Environmental and Life Sciences, 50-375 Wrocław, Poland;
| | - Krzysztof Marycz
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wrocław, Poland; (B.Q.); (A.D.); (J.K.)
- Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA 95516, USA
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Jeon S, Scorletti E, Dempsey J, Buyco D, Lin C, Saiman Y, Bayen S, Harkin J, Martin J, Hooks R, Ogretmen B, Argemi J, Melo L, Bataller R, Carr RM. Ceramide synthase 6 (CerS6) is upregulated in alcohol-associated liver disease and exhibits sex-based differences in the regulation of energy homeostasis and lipid droplet accumulation. Mol Metab 2023; 78:101804. [PMID: 37714377 PMCID: PMC10561121 DOI: 10.1016/j.molmet.2023.101804] [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: 05/26/2023] [Revised: 09/06/2023] [Accepted: 09/07/2023] [Indexed: 09/17/2023] Open
Abstract
OBJECTIVE Alcohol-associated liver disease (ALD) is the leading cause of liver-related mortality worldwide. Current strategies to manage ALD focus largely on advanced stage disease, however, metabolic changes such as glucose intolerance are apparent at the earliest stage of alcoholic steatosis and increase the risk of disease progression. Ceramides impair insulin signaling and accumulate in ALD, and metabolic pathways involving ceramide synthase 6 (CerS6) are perturbed in ALD during hepatic steatosis. In this study, we aimed to investigate the role of CerS6 in ALD development and the relevance of CerS6 to human ALD. METHODS C57BL/6 WT and CerS6 KO mice of both sexes were fed either a Lieber-DeCarli control (CON) or 15% ethanol (EtOH) diet for six weeks. In vivo metabolic tests including glucose and insulin tolerance tests (GTT and ITT) and energy expenditure were performed. The mice were euthanized, and serum and liver lipids and liver histology were examined. For in vitro studies, CerS6 was deleted in human hepatocytes, VL17A and cells were incubated with EtOH and/or C16:0-ceramides. RNAseq analysis was performed in livers from mice and human patients with different stages of ALD and diseased controls. RESULTS After six weeks on an EtOH diet, CerS6 KO mice had reduced body weight, food intake, and %fat mass compared to WT mice. Energy expenditure increased in both male and female KO mice, however, was only statistically significant in male mice. In response to EtOH, WT mice developed mild hepatic steatosis, while steatosis was ameliorated in KO mice as determined by H&E and ORO staining. KO mice showed significantly decreased long-chain ceramide species, especially C16:0-ceramides, in the serum and liver tissues compared to WT mice. CerS6 deletion decreased serum TG and NEFA only in male not female mice. CerS6 deletion improved glucose tolerance and insulin resistance in EtOH-fed mice of both sexes. RNAseq analysis revealed that 74 genes are significantly upregulated and 66 genes are downregulated by CerS6 deletion in EtOH-fed male mice, with key network pathways including TG biosynthetic process, positive regulation of lipid localization, and fat cell differentiation. Similar to RNAseq results, absence of CerS6 significantly decreased mRNA expression of lipid droplet associated proteins in EtOH-fed mice. In vitro, EtOH stimulation significantly increased PLIN2 protein expression in VL17A cells while CerS6 deletion inhibited EtOH-mediated PLIN2 upregulation. C16:0-ceramide treatment significantly increased PLIN2 protein expression compared to CON. Notably, progression of ALD in humans was associated with increased hepatic CerS6 expression. CONCLUSIONS Our findings demonstrate that CerS6 deletion improves glucose homeostasis in alcohol-fed mice and exhibits sex-based differences in the attenuation of EtOH-induced weight gain and hepatic steatosis. Additionally, we unveil that CerS6 plays a major role as a regulator of lipid droplet biogenesis in alcohol-induced intra-hepatic lipid droplet formation, identifying it as a putative target for early ALD management.
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Affiliation(s)
- Sookyoung Jeon
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA, USA; Department of Food Science & Nutrition and the Korean Institute of Nutrition, Hallym University, Chuncheon, Gangwon-do, Republic of Korea
| | - Eleonora Scorletti
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA, USA
| | - Joseph Dempsey
- Division of Gastroenterology, University of Washington, Seattle, WA, USA
| | - Delfin Buyco
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA, USA
| | - Chelsea Lin
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA, USA
| | - Yedidya Saiman
- Department of Medicine, Section of Hepatology, Lewis Katz School of Medicine Temple University, Philadelphia, PA, USA
| | - Susovon Bayen
- Division of Gastroenterology, University of Washington, Seattle, WA, USA
| | - Julia Harkin
- Division of Gastroenterology, University of Washington, Seattle, WA, USA
| | - Jasmin Martin
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA, USA
| | - Royce Hooks
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA, USA
| | - Besim Ogretmen
- Department of Biochemistry and Molecular Biology, and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Josepmaria Argemi
- Center for Liver Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Luma Melo
- Center for Liver Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Ramon Bataller
- Center for Liver Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Rotonya M Carr
- Division of Gastroenterology, University of Washington, Seattle, WA, USA.
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Abstract
The steatotic diseases of metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and chronic hepatitis C (HCV) account for the majority of liver disease prevalence, morbidity, and mortality worldwide. While these diseases have distinct pathogenic and clinical features, dysregulated lipid droplet (LD) organelle biology represents a convergence of pathogenesis in all three. With increasing understanding of hepatocyte LD biology, we now understand the roles of LD proteins involved in these diseases but also how genetics modulate LD biology to either exacerbate or protect against the phenotypes associated with steatotic liver diseases. Here, we review the history of the LD organelle and its biogenesis and catabolism. We also review how this organelle is critical not only for the steatotic phenotype of liver diseases but also for their advanced phenotypes. Finally, we summarize the latest attempts and challenges of leveraging LD biology for therapeutic gain in steatotic diseases. In conclusion, the study of dysregulated LD biology may lead to novel therapeutics for the prevention of disease progression in the highly prevalent steatotic liver diseases of MASLD, ALD, and HCV.
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Affiliation(s)
- Joseph L Dempsey
- Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington
| | - George N Ioannou
- Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington
- Division of Gastroenterology, Veterans Affairs Puget Sound Healthcare System Seattle, Washington
| | - Rotonya M Carr
- Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington
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Patel S, Kim RG, Shui AM, Magee C, Lu M, Chen J, Tana M, Huang CY, Khalili M. Fatty Liver Education Promotes Physical Activity in Vulnerable Groups, Including Those With Unhealthy Alcohol Use. GASTRO HEP ADVANCES 2023; 3:84-94. [PMID: 39100862 PMCID: PMC11293529 DOI: 10.1016/j.gastha.2023.09.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 09/28/2023] [Indexed: 08/06/2024]
Abstract
BACKGROUND AND AIMS Fatty liver disease (FLD), alcohol-associated and metabolically associated, often coexists. Increase in physical activity is associated with metabolic health and decreased FLD. We aimed to identify factors associated with physical activity and its improvement following FLD education in a racially diverse, vulnerable population. METHODS From February 19, 2020 to December 30, 2022, 314 adults with FLD at safety-net hepatology clinics in San Francisco were surveyed at baseline, immediately after FLD education, and at 6-month follow-up. After collecting clinical and sociodemographic data, logistic regression (adjusted for age, sex, and race/ethnicity) assessed factors associated with physical activity at baseline and its improvement following education. RESULTS Participant characteristics in those without vs with any physical activity were median age 49 vs 55 years, 64% vs 56% female, 66% vs 53% Hispanic race/ethnicity, 75% vs 55% obese, and 30% vs 22% consumed heavy alcohol, respectively. On multivariable analysis, older age was the only significant factor associated with physical activity at baseline (relative risk ratio 1.37 per decade increase, 95% confidence interval [CI] 1.07-1.75). Hispanic (vs non-Hispanic) participants had a significantly higher odds of improvement in physical activity (vs no change) 6 months after education (odds ratio 2.36, 95% CI 1.27-4.39). Among those with suboptimal or no physical activity at baseline, participants who consumed heavy alcohol (vs no drinking) had a significantly higher likelihood of achieving optimal physical activity following education (relative risk ratio 1.98, 95% CI 1.05-3.74). CONCLUSION Despite social and structural barriers, FLD education increased uptake of physical activity in vulnerable populations, especially among Hispanic individuals and those consuming heavy alcohol. Implementation of patient-centered education is important for FLD management.
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Affiliation(s)
- Shyam Patel
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Francisco, San Francisco, California
- Division of Gastroenterology and Hepatology, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, California
| | - Rebecca G. Kim
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Francisco, San Francisco, California
- Division of Gastroenterology and Hepatology, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, California
| | - Amy M. Shui
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California
| | - Catherine Magee
- Division of Gastroenterology and Hepatology, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, California
| | - Maggie Lu
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Francisco, San Francisco, California
- Division of Gastroenterology and Hepatology, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, California
| | - Jennifer Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Francisco, San Francisco, California
- Division of Gastroenterology and Hepatology, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, California
| | - Michele Tana
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Francisco, San Francisco, California
- Division of Gastroenterology and Hepatology, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, California
| | - Chiung-Yu Huang
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California
| | - Mandana Khalili
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Francisco, San Francisco, California
- Division of Gastroenterology and Hepatology, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, California
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Song J, Choi S, Park SJ, Kim SM, Cho Y, Lee G, Kim JS, Park SM. Association of the amount of alcohol consumption with change in skeletal muscle and fat mass among Korean adults. Alcohol 2023; 111:9-16. [PMID: 37054822 DOI: 10.1016/j.alcohol.2023.04.003] [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: 01/30/2023] [Revised: 04/03/2023] [Accepted: 04/04/2023] [Indexed: 04/15/2023]
Abstract
The association between changes in alcohol consumption and body composition remains unclear. We investigated the association between changes in drinking habits and muscle mass and fat mass in adults. From the Health Examinees in Korea, the study population (N = 62 094) was categorized according to alcohol consumption (g of ethanol/day) and the changes in drinking habits between the baseline and follow-up periods were determined. Predicted muscle mass index (pMM), lean mass index, and fat mass index (pFM) were also calculated using age, sex, weight, height, and waist circumference. The β coefficient and adjusted means were then calculated using multiple linear regression analysis after adjusting for covariates, including follow-up duration, calorie intake, and protein intake. Compared to the almost-unchanged drinking group (reference; adjusted mean: -0.030 [95% confidence intervals: -0.048, -0.011]), there was no statistical difference or tendency of change in the pMMs of the most-decreased (-0.024 [-0.048, 0.000]) and the most-increased (-0.027 [-0.059, -0.013]) alcohol-consumed groups. The pFM decreased at those with less alcohol consumption (0.053 [-0.011, 0.119]) and increased with increased alcohol consumption (0.125 [0.063, 0.187]), compared to the no-change group (reference; 0.088 [0.036, 0.140]). Thus, changes in alcohol consumption were not significantly associated with changes in muscle mass. Increased alcohol consumption was associated with increased fat mass. Reducing the amount of alcohol consumption may improve body composition in terms of fat mass.
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Affiliation(s)
- Jihun Song
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea
| | - Seulggie Choi
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Sun Jae Park
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea
| | - Sung Min Kim
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea
| | - Yoosun Cho
- Total Healthcare Center, Kangbuk Samsung Hospital, School of Medicine, Sungkyunkwan University, Seoul, Republic of Korea
| | - Gyeongsil Lee
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea; Medical Food R&D Center, Esther Formula, Seoul, Republic of Korea
| | - Ji Soo Kim
- International Healthcare Center, Seoul National University Hospital, Seoul, Republic of Korea
| | - Sang Min Park
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea; Department of Family Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
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11
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Okpujie V, Tobalesi O, Uwumiro F, Ugoh AC, Osiogo EO, Abesin O, Olaomi OA, Nwevo CO, Ayantoyinbo T, Ejeagha F. The Influence of Insulin Resistance on Outcomes in Hospitalizations for Alcohol-Related Liver Disease: A Nationwide Study. Cureus 2023; 15:e42964. [PMID: 37667704 PMCID: PMC10475319 DOI: 10.7759/cureus.42964] [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: 08/04/2023] [Indexed: 09/06/2023] Open
Abstract
Background Alcoholic liver disease (ALD) is known to contribute to the onset of insulin resistance (IR), which has been speculated to worsen the outcome of the disease. This study examines the impact of IR on the severity and outcomes of hospitalizations for ALD. Methods A retrospective study was performed using the combined 2016 to 2018 Nationwide Inpatient Sample. All admissions for ALD were included. The association between IR and the clinical and resource utilization of hospitalizations for ALD was analyzed using multivariate regression models to adjust for confounding variables. Results About 294,864 hospitalizations for ALD were analyzed. Of these, 383 cases (0.13%) included a secondary diagnosis of IR, while the remaining 294,481 hospitalizations (99.87%) were considered as controls. The incidence of IR in the study was 1.3 per 1000 admissions for ALD. IR was not associated with any significant difference in the likelihood of mortality (adjusted odds ratio (aOR): 1.10, 95% confidence interval (CI): 0.370-3.251, p=0.867), acute liver failure, or the incidence of complications (aOR: 0.83, 95% CI: 0.535-1.274, p<0.001). However, the study found that ALD hospitalizations with IR had longer hospital stays (7.3 days vs. 6.0 days: IRR, 1.17; 95% CI, 1.09-1.26; p<0.001) and higher mean hospital costs ($91,124 vs. $65,290: IRR, 1.32; 95% CI, 1.20-1.46; p<0.001) compared to patients without IR. Conclusion IR alone does not worsen the outcomes of patients with ALD, and its association with longer hospital stays and higher mean hospital costs could be due to other confounding factors.
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Affiliation(s)
| | - Opeyemi Tobalesi
- Internal Medicine, College of Health Sciences, University of Ilorin, Ilorin, NGA
| | | | - Amaka C Ugoh
- Internal Medicine, University of Benin Teaching Hospital, Benin, NGA
| | - Elsie O Osiogo
- Internal Medicine, Ahmadu Bello University Teaching Hospital, Zaria, NGA
| | - Olawale Abesin
- Internal Medicine, Royal Cornwall Hospital NHS Trust, Truro, GBR
| | | | - Chimaobi O Nwevo
- Medicine and Surgery, University of Calabar Teaching Hospital, Calabar, NGA
| | - Tosin Ayantoyinbo
- Internal Medicine, Obafemi Awolowo College of Health Sciences, Olabisi Onabanjo University, Ife, NGA
| | - Franklin Ejeagha
- Internal Medicine, University of Nigeria Teaching Hospital, Enugu, NGA
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12
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Buyco DG, Dempsey JL, Scorletti E, Jeon S, Lin C, Harkin J, Bayen S, Furth EE, Martin J, Delima M, Hooks R, Sostre-Colón J, Gharib SA, Titchenell PM, Carr RM. Concomitant western diet and chronic-binge alcohol dysregulate hepatic metabolism. PLoS One 2023; 18:e0281954. [PMID: 37134024 PMCID: PMC10155975 DOI: 10.1371/journal.pone.0281954] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 02/03/2023] [Indexed: 05/04/2023] Open
Abstract
BACKGROUND AND AIMS There is significant overlap between non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) with regards to risk factors and disease progression. However, the mechanism by which fatty liver disease arises from concomitant obesity and overconsumption of alcohol (syndrome of metabolic and alcohol-associated fatty liver disease; SMAFLD), is not fully understood. METHODS Male C57BL6/J mice were fed chow diet (Chow) or high-fructose, high-fat, high-cholesterol diet (FFC) for 4 weeks, then administered either saline or ethanol (EtOH, 5% in drinking water) for another 12 weeks. The EtOH treatment also consisted of a weekly 2.5 g EtOH/kg body weight gavage. Markers for lipid regulation, oxidative stress, inflammation, and fibrosis were measured by RT-qPCR, RNA-seq, Western blot, and metabolomics. RESULTS Combined FFC-EtOH induced more body weight gain, glucose intolerance, steatosis, and hepatomegaly compared to Chow, EtOH, or FFC. Glucose intolerance by FFC-EtOH was associated with decreased hepatic protein kinase B (AKT) protein expression and increased gluconeogenic gene expression. FFC-EtOH increased hepatic triglyceride and ceramide levels, plasma leptin levels, hepatic Perilipin 2 protein expression, and decreased lipolytic gene expression. FFC and FFC-EtOH also increased AMP-activated protein kinase (AMPK) activation. Finally, FFC-EtOH enriched the hepatic transcriptome for genes involved in immune response and lipid metabolism. CONCLUSIONS In our model of early SMAFLD, we observed that the combination of an obesogenic diet and alcohol caused more weight gain, promoted glucose intolerance, and contributed to steatosis by dysregulating leptin/AMPK signaling. Our model demonstrates that the combination of an obesogenic diet with a chronic-binge pattern alcohol intake is worse than either insult alone.
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Affiliation(s)
- Delfin Gerard Buyco
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Joseph L. Dempsey
- Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington, United States of America
| | - Eleonora Scorletti
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Sookyoung Jeon
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
- Department of Food Science and Nutrition, Hallym University, Chuncheon, Gangwon-do, Republic of Korea
| | - Chelsea Lin
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Julia Harkin
- Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington, United States of America
| | - Susovon Bayen
- Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington, United States of America
| | - Emma E. Furth
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Jasmin Martin
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Monique Delima
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Royce Hooks
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Jaimarie Sostre-Colón
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Sina A. Gharib
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, Washington, United States of America
- Center for Lung Biology, University of Washington, Seattle, Washington, United States of America
| | - Paul M. Titchenell
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
- Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Rotonya M. Carr
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
- Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington, United States of America
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13
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Roy JR, Janaki CS, Jayaraman S, Veeraraghavan VP, Periyasamy V, Balaji T, Vijayamalathi M, Bhuvaneswari P, Swetha P. Hypoglycemic Potential of Carica papaya in Liver Is Mediated through IRS-2/PI3K/SREBP-1c/GLUT2 Signaling in High-Fat-Diet-Induced Type-2 Diabetic Male Rats. TOXICS 2023; 11:240. [PMID: 36977005 PMCID: PMC10054599 DOI: 10.3390/toxics11030240] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 02/26/2023] [Accepted: 02/26/2023] [Indexed: 06/18/2023]
Abstract
Regardless of socioeconomic or demographic background, the prevalence of type 2 diabetes mellitus, which affects more than half a billion people worldwide, has been steadily increasing over time. The health, emotional, sociological, and economic well-being of people would suffer if this number is not successfully handled. The liver is one of the key organs accountable for sustaining metabolic balance. Elevated levels of reactive oxygen species inhibit the recruitment and activation of IRS-1, IRS-2, and PI3K-Akt downstream signaling cascade. These signaling mechanisms reduce hepatic glucose absorption and glycogenesis while increasing hepatic glucose output and glycogenolysis. In our work, an analysis of the molecular mechanism of Carica papaya in mitigating hepatic insulin resistance in vivo and in silico was carried out. The gluconeogenic enzymes, glycolytic enzymes, hepatic glycogen tissue concentration, oxidative stress markers, enzymatic antioxidants, protein expression of IRS-2, PI3K, SREBP-1C, and GLUT-2 were evaluated in the liver tissues of high-fat-diet streptozotocin-induced type 2 diabetic rats using q-RT-PCR as well as immunohistochemistry and histopathology. Upon treatment, C. papaya restored the protein and gene expression in the liver. In the docking analysis, quercetin, kaempferol, caffeic acid, and p-coumaric acid present in the extract were found to have high binding affinities against IRS-2, PI3K, SREBP-1c, and GLUT-2, which may have contributed much to the antidiabetic property of C. papaya. Thus, C. papaya was capable of restoring the altered levels in the hepatic tissues of T2DM rats, reversing hepatic insulin resistance.
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Affiliation(s)
- Jeane Rebecca Roy
- Department of Anatomy, Bhaarath Medical College and Hospital, Bharath Institute of Higher Education and Research (BIHER), Chennai 600 073, Tamil Nadu, India
| | - Coimbatore Sadagopan Janaki
- Department of Anatomy, Bhaarath Medical College and Hospital, Bharath Institute of Higher Education and Research (BIHER), Chennai 600 073, Tamil Nadu, India
| | - Selvaraj Jayaraman
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical & Technical Sciences, Saveetha University, Chennai 600 077, Tamil Nadu, India
| | - Vishnu Priya Veeraraghavan
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical & Technical Sciences, Saveetha University, Chennai 600 077, Tamil Nadu, India
| | - Vijayalakshmi Periyasamy
- Department of Biotechnology and Bioinformatics, Holy Cross College, Trichy 620 002, Tamil Nadu, India
| | - Thotakura Balaji
- Department of Anatomy, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Chennai 603 103, Tamil Nadu, India
| | - Madhavan Vijayamalathi
- Department of Physiology, Bhaarath Medical College and Hospital, Bharath Institute of Higher Education and Research (BIHER), Chennai 600 073, Tamil Nadu, India
| | - Ponnusamy Bhuvaneswari
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical & Technical Sciences, Saveetha University, Chennai 600 077, Tamil Nadu, India
| | - Panneerselvam Swetha
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical & Technical Sciences, Saveetha University, Chennai 600 077, Tamil Nadu, India
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14
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Louvet A, Bourcier V, Archambeaud I, d'Alteroche L, Chaffaut C, Oberti F, Moreno C, Roulot D, Dao T, Moirand R, Duclos-Vallée JC, Goria O, Nguyen-Khac E, Pol S, Carbonell N, Gournay J, Elkrief L, Fouchard-Hubert I, Chevret S, Ganne-Carrié N. Low alcohol consumption influences outcomes in individuals with alcohol-related compensated cirrhosis in a French multicenter cohort. J Hepatol 2023; 78:501-512. [PMID: 36423805 DOI: 10.1016/j.jhep.2022.11.013] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 10/24/2022] [Accepted: 11/04/2022] [Indexed: 11/23/2022]
Abstract
BACKGROUND & AIMS The harmful impact of heavy alcohol consumption and recurrence in patients with alcohol-related cirrhosis is long-established, although this is based on old studies. However, the drivers of long-term outcome still need to be clearly investigated. METHOD All patients with biopsy-proven compensated alcohol-related cirrhosis included in the CIRRAL cohort (22 centers) were prospectively studied. Prognostic variables of survival and liver event-free survival were assessed using multivariable Cox models with stepwise selection. The prognostic impact of alcohol recurrence during follow-up (computed in glass-years in the same way as pack-years for tobacco) was assessed using a time-dependent covariable. RESULTS From 2010 to 2016, 650 patients were included. The median age at baseline was 58.4 years, 67.4% were men and the median BMI was 27.8 kg/m2, 63.8% had a history of liver decompensation, and 70.2% had discontinued alcohol. At 5 years, recurrence occurred in 30.9% of abstinent patients and this risk was higher in patients with a history of drug abuse and in those with shorter alcohol discontinuation times. Median survival was 97 months. Age, alcohol consumption at baseline, platelet count and Child-Pugh score >5 were associated with overall and liver event-free survival on multivariate analysis. Alcohol consumption of more than 25 glass-years during follow-up was independently associated with lower survival and with a trend toward lower liver event-free survival, with the risk increasing from 1 glass-year, though not significantly. Simon & Makuch plots confirm the benefit of no alcohol consumption (<1 glass/week) on both outcomes and the dose-dependent impact of alcohol over time. CONCLUSION This prospective study in patients with compensated alcohol-related cirrhosis identifies factors predictive of alcohol recurrence during follow-up and shows that moderate alcohol consumption during follow-up negatively impacts outcomes. Patients with alcohol-related cirrhosis should be advised to completely stop drinking alcohol. REGISTRATION CIRRAL (NCT01213927) cohort was registered at ClinicalTrials.gov and the full protocol is available at the following link: https://clinicaltrials.gov/ct2/show/NCT01213927. IMPACT AND IMPLICATIONS In patients with alcohol-related cirrhosis, data are lacking about the impact of the amount of alcohol consumed on both survival and liver-related events. The present study based on the CIRRAL cohort demonstrates that alcohol recurrence occurs in more than 30% of patients with compensated cirrhosis and that even a moderate recurrence strongly influences outcomes. Patients with compensated alcohol-related cirrhosis should be advised to completely discontinue alcohol consumption, even in small amounts, as the present study shows that no alcohol consumption can be regarded as safe when cirrhosis has developed.
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Affiliation(s)
| | - Valérie Bourcier
- AP-HP, Hôpital Avicenne, Service d'Hépatologie, Bobigny, Université Sorbonne Paris Nord, Bobigny et INSERM U1138, Université de Paris, France
| | | | | | - Cendrine Chaffaut
- SBIM, APHP, Hôpital Saint-Louis, Paris, Inserm, UMR-1153, ECSTRRA Team, Paris, France
| | | | | | - Dominique Roulot
- AP-HP, Hôpital Avicenne, Service d'Hépatologie, Bobigny, Université Sorbonne Paris Nord, Bobigny et INSERM U1138, Université de Paris, France; Inserm U955 Université Paris Est, Créteil, France
| | - Thông Dao
- Liver Unit, University Hospital, Caen, France
| | | | | | - Odile Goria
- Liver Unit, University Hospital, Rouen, France
| | | | - Stanislas Pol
- Liver Unit, Hôpital Cochin, INSERM U1223, Institut Pasteur, Paris, France
| | | | | | | | | | - Sylvie Chevret
- SBIM, APHP, Hôpital Saint-Louis, Paris, Inserm, UMR-1153, ECSTRRA Team, Paris, France
| | - Nathalie Ganne-Carrié
- AP-HP, Hôpital Avicenne, Service d'Hépatologie, Bobigny, Université Sorbonne Paris Nord, Bobigny et INSERM U1138, Université de Paris, France.
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15
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Habib S, Murakami T, Takyar V, Patel K, Dominguez C, Zhan Y, Mehrpour O, Hsu CH. The Impact of Metabolic Syndrome on the Prognosis of High-Risk Alcoholic Hepatitis Patients: Redefining Alcoholic Hepatitis. Gastroenterology Res 2023; 16:25-36. [PMID: 36895697 PMCID: PMC9990531 DOI: 10.14740/gr1556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 10/03/2022] [Indexed: 03/11/2023] Open
Abstract
Background Alcoholic hepatitis (AH) is characterized by acute symptomatic hepatitis associated with heavy alcohol use. This study was designed to assess the impact of metabolic syndrome on high-risk patients with AH with discriminant function (DF) score ≥ 32 and its effect on mortality. Methods We searched the hospital database for ICD-9 diagnosis codes of acute AH, alcoholic liver cirrhosis, and alcoholic liver damage. The entire cohort was categorized into two groups: AH and AH with metabolic syndrome. The effect of metabolic syndrome on mortality was evaluated. Also, an exploratory analysis was used to create a novel risk measure score to assess mortality. Results A large proportion (75.5%) of the patients identified in the database who had been treated as AH had other etiologies and did not meet the American College of Gastroenterology (ACG)-defined diagnosis of acute AH, thus had been misdiagnosed as AH. Such patients were excluded from analysis. The mean body mass index (BMI), hemoglobin (Hb), hematocrit (HCT), and alcoholic liver disease/non-alcoholic fatty liver disease index (ANI) were significantly different between two groups (P < 0.05). The results of a univariate Cox regression model showed that age, BMI, white blood cells (WBCs), creatinine (Cr), international normalized ratio (INR), prothrombin time (PT), albumin levels, albumin < 3.5, total bilirubin, Na, Child-Turcotte-Pugh (CTP), model for end-stage liver disease (MELD), MELD ≥ 21, MELD ≥ 18, DF score, and DF ≥ 32 had a significant effect on mortality. Patients with a MELD greater than 21 had a hazard ratio (HR) (95% confidence interval (CI) of 5.81 (2.74 - 12.30) (P < 0.001). The adjusted Cox regression model results showed that age, Hb, Cr, INR, Na, MELD score, DF score, and metabolic syndrome were independently associated with high patient mortality. However, the increase in BMI and mean corpuscular volume (MCV) and sodium significantly reduced the risk of death. We found that a model including age, MELD ≥ 21, and albumin < 3.5 was the best model in identifying patient mortality. Our study showed that patients admitted with a diagnosis of alcoholic liver disease with metabolic syndrome had an increased mortality risk compared to patients without metabolic syndrome, in high-risk patients with DF ≥ 32 and MELD ≥ 21. A bivariate correlation analysis revealed that patients with AH with metabolic syndrome were more likely to have infection (43%) compared to AH (26%) with correlation coefficient of 0.176 (P = 0.03, CI: 0.018 - 1.0). Conclusion In clinical practice, the diagnosis of AH is inaccurately applied. Metabolic syndrome significantly increases the mortality risk in high-risk AH. It signifies that the presence of features of metabolic syndrome modifies the behavior of AH in acute settings, warranting different therapeutic strategies. We propose that in defining AH, patients overlapping with metabolic syndrome may need to be excluded as their outcome is different with regard to risk of renal dysfunctions, infections and death.
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Affiliation(s)
| | | | | | | | | | - Yongcheng Zhan
- Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA
| | | | - Chiu-Hsieh Hsu
- Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA
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16
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Adekunle AD, Adejumo A, Singal AK. Therapeutic targets in alcohol-associated liver disease: progress and challenges. Therap Adv Gastroenterol 2023; 16:17562848231170946. [PMID: 37187673 PMCID: PMC10176580 DOI: 10.1177/17562848231170946] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 04/04/2023] [Indexed: 05/17/2023] Open
Abstract
Alcohol-associated liver disease (ALD) is a complex disease with rapidly increasing prevalence. Although there are promising therapeutic targets on the horizon, none of the newer targets is currently close to an Food and Drug Administration approval. Strategies are needed to overcome challenges in study designs and conducting clinical trials and provide impetus to the field of drug development in the landscape of ALD and alcoholic hepatitis. Management of ALD is complex and should include therapies to achieve and maintain alcohol abstinence, preferably delivered by a multidisciplinary team. Although associated with clear mortality benefit in select patients, the use of early liver transplantation still requires refinement to create uniformity in selection protocols across transplant centers. There is also a need for reliable noninvasive biomarkers for prognostication. Last but not the least, strategies are urgently needed to implement integrated multidisciplinary care models for treating the dual pathology of alcohol use disorder and of liver disease for improving the long-term outcomes of patients with ALD.
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Affiliation(s)
- Ayooluwatomiwa Deborah Adekunle
- Department of Internal Medicine, St. Luke’s
Hospital, Chesterfield, Missouri, USA
- Division of Hepatology, University of
Pittsburgh Medical Center, Pittsburgh, PA, USA
- Division of Transplant Hepatology, University
of South Dakota Sanford Medical School, Sioux Falls, SD
| | - Adeyinka Adejumo
- Department of Internal Medicine, St. Luke’s
Hospital, Chesterfield, Missouri, USA
- Division of Hepatology, University of
Pittsburgh Medical Center, Pittsburgh, PA, USA
- Division of Transplant Hepatology, University
of South Dakota Sanford Medical School, Sioux Falls, SD
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17
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Lee JH, Kwon YJ, Lee HS, Han JH, Joung B, Kim SJ. Fatty Liver Is an Independent Risk Factor for Elevated Intraocular Pressure. Nutrients 2022; 14:nu14214455. [PMID: 36364718 PMCID: PMC9657431 DOI: 10.3390/nu14214455] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 10/14/2022] [Accepted: 10/20/2022] [Indexed: 12/02/2022] Open
Abstract
Elevated intraocular pressure (EIOP) is a major risk factor for glaucoma. Both EIOP and fatty liver share metabolic risk factors, which implies a possible link between EIOP and fatty liver. We aimed to determine the association of fatty liver with EIOP and estimate the effect of fatty liver on EIOP directly and indirectly through insulin resistance. Data from 16,240 adults who underwent health examinations at a single center were analyzed. Multiple logistic regression analyses revealed that fully adjusted odds ratio (OR) and 95% confidence interval (CI) for EIOP in the fatty liver group compared to the non-fatty liver group were 1.36 and 1.08-1.71. Alcoholic liver disease was associated with EIOP in subgroup analysis (OR = 1.80, 95% CI: 1.27-2.56). There was a linear dose-response relationship between EIOP and the severity of fatty liver. Mediation analysis revealed that the total effect of fatty liver on intraocular pressure was 0.90 (0.81-0.99), with a direct effect of 0.81 (0.71-0.90) and an indirect effect of 0.09 (0.06-0.11) through insulin resistance. Fatty liver is independently associated with EIOP. It primarily has a direct effect on intraocular pressure. This suggests that evaluation of EIOP should be considered in patients with fatty liver.
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Affiliation(s)
- Jun-Hyuk Lee
- Nowon Eulji Medical Center, Department of Family Medicine, Eulji University School of Medicine, Seoul 01830, Korea
- Department of Medicine, Graduate School of Hanyang University, Seoul 04763, Korea
| | - Yu-Jin Kwon
- Department of Family Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Seoul 16995, Korea
| | - Hye Sun Lee
- Biostatistics Collaboration Unit, Department of Research Affairs, Yonsei University College of Medicine, Seoul 06273, Korea
| | - Jee Hye Han
- Nowon Eulji Medical Center, Department of Family Medicine, Eulji University School of Medicine, Seoul 01830, Korea
| | - Boyoung Joung
- Department of Internal Medicine, Division of Cardiology, Yonsei University College of Medicine, Seoul 03722, Korea
- Correspondence: (B.J.); (S.J.K.); Tel.: +82-2-2228-8460 (B.J.); +82-2-970-8322 (S.J.K.)
| | - Sung Jin Kim
- Nowon Eulji Medical Center, Department of Ophthalmology, Eulji University School of Medicine, Seoul 01830, Korea
- Correspondence: (B.J.); (S.J.K.); Tel.: +82-2-2228-8460 (B.J.); +82-2-970-8322 (S.J.K.)
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18
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Alcohol-Related Liver Disease: An Overview on Pathophysiology, Diagnosis and Therapeutic Perspectives. Biomedicines 2022; 10:biomedicines10102530. [PMID: 36289791 PMCID: PMC9599689 DOI: 10.3390/biomedicines10102530] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/01/2022] [Accepted: 10/08/2022] [Indexed: 11/19/2022] Open
Abstract
Alcohol-related liver disease (ALD) refers to a spectrum of liver manifestations ranging from fatty liver diseases, steatohepatitis, and fibrosis/cirrhosis with chronic inflammation primarily due to excessive alcohol use. Currently, ALD is considered as one of the most prevalent causes of liver disease-associated mortality worldwide. Although the pathogenesis of ALD has been intensively investigated, the present understanding of its biomarkers in the context of early clinical diagnosis is not complete, and novel therapeutic targets that can significantly alleviate advanced forms of ALD are limited. While alcohol abstinence remains the primary therapeutic intervention for managing ALD, there are currently no approved medications for treating ALD. Furthermore, given the similarities and the differences between ALD and non-alcoholic fatty liver disease in terms of disease progression and underlying molecular mechanisms, numerous studies have demonstrated that many therapeutic interventions targeting several signaling pathways, including oxidative stress, inflammatory response, hormonal regulation, and hepatocyte death play a significant role in ALD treatment. Therefore, in this review, we summarized several key molecular targets and their modes of action in ALD progression. We also described the updated therapeutic options for ALD management with a particular emphasis on potentially novel signaling pathways.
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Way GW, Jackson KG, Muscu SR, Zhou H. Key Signaling in Alcohol-Associated Liver Disease: The Role of Bile Acids. Cells 2022; 11:1374. [PMID: 35456053 PMCID: PMC9031669 DOI: 10.3390/cells11081374] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/11/2022] [Accepted: 04/14/2022] [Indexed: 02/01/2023] Open
Abstract
Alcohol-associated liver disease (ALD) is a spectrum of diseases, the onset and progression of which are due to chronic alcohol use. ALD ranges, by increasing severity, from hepatic steatosis to alcoholic hepatitis (AH) and alcohol-associated cirrhosis (AC), and in some cases, can lead to the development of hepatocellular carcinoma (HCC). ALD continues to be a significant health burden and is now the main cause of liver transplantations in the United States. ALD leads to biological, microbial, physical, metabolic, and inflammatory changes in patients that vary depending on disease severity. ALD deaths have been increasing in recent years and are projected to continue to increase. Current treatment centers focus on abstinence and symptom management, with little in the way of resolving disease progression. Due to the metabolic disruption and gut dysbiosis in ALD, bile acid (BA) signaling and metabolism are also notably affected and play a prominent role in disease progression in ALD, as well as other liver disease states, such as non-alcoholic fatty liver disease (NAFLD). In this review, we summarize the recent advances in the understanding of the mechanisms by which alcohol consumption induces hepatic injury and the role of BA-mediated signaling in the pathogenesis of ALD.
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Affiliation(s)
- Grayson W. Way
- Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Kaitlyn G. Jackson
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA; (K.G.J.); (S.R.M.)
| | - Shreya R. Muscu
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA; (K.G.J.); (S.R.M.)
| | - Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA; (K.G.J.); (S.R.M.)
- Central Virginia Veterans Healthcare System, Richmond, VA 23249, USA
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20
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Anti-Inflammatory Dietary Approach to Prevent the Development and Progression of Non-Alcoholic Fatty Liver Diseases. LIVERS 2022. [DOI: 10.3390/livers2010005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an increasing health problem worldwide and is associated with insulin resistance, increased visceral fat mass, and cardiovascular problems. Lifestyle factors such as sedentary lifestyle, chronic stress, obesogenic environment as well as a Western pattern diet are main contributors to the development and progression of this disease. In particular, the diet plays a pivotal role. An unhealthy diet including high consumption of red and processed meats, refined carbohydrates, simple sugars, highly processed foods with food additives and conservatives are lighting the fire for a low-grade inflammation. If other risk factors come into play, metabolic and hormonal derangement may occur, leading to the increase in visceral fat, gut dysbiosis and leaky gut, which stoke the inflammatory fire. Thus, lifestyle interventions are the most effective approach to quell the inflammatory processes. An anti-inflammatory and low-glycemic diet named the GLykLich diet, which includes whole and unprocessed foods, may reduce the risk of increased morbidity and mortality. The GLykLich diet suggests a meal consisting of complex carbohydrates (fiber), good quality of protein and healthy fats (DHA/EPA), and is rich in secondary plant products. There is no single nutrient to prevent the progression of NAFLD, rather, it is the complexity of substances in whole unprocessed foods that reduce the inflammatory process, improve metabolic state, and thus reverse NAFLD.
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21
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Kim RG, Kramer-Feldman J, Bacchetti P, Grimes B, Burchard E, Eng C, Hu D, Hellerstein M, Khalili M. Disentangling the impact of alcohol use and hepatitis C on insulin action in Latino individuals. Alcohol Clin Exp Res 2022; 46:87-99. [PMID: 34773280 PMCID: PMC8799492 DOI: 10.1111/acer.14743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 10/18/2021] [Accepted: 11/09/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND Alcohol, insulin resistance (IR), and hepatitis C (HCV) are all significant contributors to adverse outcomes of chronic liver disease. Latinos are disproportionately affected by these risk factors. We investigated the relationship between alcohol use and insulin action in a prospective cohort of Latino individuals with and without HCV. METHODS One hundred fifty-three nondiabetic Latino individuals (60 HCV+, 93 HCV-) underwent clinical evaluation and metabolic testing; 56 had repeat testing over a median follow-up of 1.5 years. Peripheral IR and hepatic IR were measured via steady-state plasma glucose (SSPG) and endogenous glucose production during a two-step, 240-min insulin suppression test. Insulin secretion (IS) was measured using the graded glucose infusion test. Alcohol use was categorized as none, moderate (≤1 drink/day for women and ≤2 drinks/day for men), and heavy (>moderate). Multivariable models including HCV status assessed associations of alcohol use with baseline SSPG, hepatic IR and IS, and changes in these parameters over time. RESULTS Overall, the median age was 44 years, 63.4% were male, 66.7% overweight/ obese, and 31.9% had heavy lifetime alcohol use while 60.4% had moderate lifetime alcohol use. SSPG and IS were similar by levels of alcohol use at baseline and alcohol use was not statistically significantly associated with change in these measures over time. However, lifetime daily heavy alcohol use (vs. not heavy, coef 2.4 μU-mg/kg-min-ml, p = 0.04) and HCV status (coef 4.4 μU-mg/kg-min-ml, p = 0.0003) were independently associated with higher baseline hepatic IR, and current heavy alcohol use was associated with greater change in hepatic IR in follow-up (coef 5.8 μU-mg/kg-min-ml, p = 0.03). CONCLUSIONS In this cohort of Latino individuals, lifetime and current heavy alcohol use influenced hepatic IR and its change over time. Strategies to decrease rates of heavy alcohol use or increase abstinence along with lifestyle modification and anti-HCV therapy to reduce metabolic risk are critical to prevent adverse liver and metabolic outcomes in Latino individuals.
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Affiliation(s)
- Rebecca G Kim
- Department of Medicine, Division of Gastroenterology and Hepatology, University of California, San Francisco, San Francisco, CA
| | - Jonathan Kramer-Feldman
- Department of Medicine, Division of Gastroenterology and Hepatology, University of California, San Francisco, San Francisco, CA
| | - Peter Bacchetti
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA
| | - Barbara Grimes
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA
| | - Esteban Burchard
- Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - Celeste Eng
- Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - Donglei Hu
- Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - Marc Hellerstein
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA
| | - Mandana Khalili
- Department of Medicine, Division of Gastroenterology and Hepatology, University of California, San Francisco, San Francisco, CA,Liver Center, University of California San Francisco, San Francisco, CA
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22
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Zhang Y, Lu J, Zhong YJ, Yang CF, Chen L, Wu D, Song MW, Shi L, Ma ZH, Li L, Li YW. Methyl ferulic acid ameliorates alcohol-induced hepatic insulin resistance via miR-378b-mediated activation of PI3K-AKT pathway. Biomed Pharmacother 2021; 145:112462. [PMID: 34844105 DOI: 10.1016/j.biopha.2021.112462] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/13/2021] [Accepted: 11/19/2021] [Indexed: 12/18/2022] Open
Abstract
A previous study indicated that microRNA-378b (miR-378b) plays a critical role in controlling hepatic insulin resistance by targeting insulin receptor (IR) and p110α in alcoholic liver disease (ALD). Methyl ferulic acid (MFA), a bioactive ingredient in Securidaca inappendiculata Hassk rhizomes, exhibits multiple pharmacological activities. It has been reported that MFA ameliorates insulin resistance in ALD, whereas the underlying molecular mechanism remains unclear. The objective of study was to evaluate the influence of MFA on insulin sensitivity in ethanol-induced L-02 cells as well as alcohol-fed mice and illuminate the function of miR-378b-mediated phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway in system. MFA was found to remarkably down-regulate miR-378b level and increase IR and p110α expressions. Furthermore, the effect of MFA on modulating miR-378b/PI3K-AKT pathway to enhance insulin sensitivity was corroborated by overexpressing and inhibiting miR-378b. Taken together, MFA exhibited a positive effect against ALD by attenuating the inhibition of miR-378b on IR/p110α and partly activating the insulin signaling to alleviate alcohol-induced hepatic insulin resistance.
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Affiliation(s)
- Yan Zhang
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Jun Lu
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Yu-Juan Zhong
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Cheng-Fang Yang
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Li Chen
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Dan Wu
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Meng-Wei Song
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Lin Shi
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Zu-Heng Ma
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
| | - Li Li
- College of Pharmacy, Guilin Medical University, Guilin, China.
| | - Yong-Wen Li
- College of Pharmacy, Guilin Medical University, Guilin, China; Center for Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin, China.
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23
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Asiedu B, Nyakudya TT, Lembede BW, Chivandi E. Early-life exposure to alcohol and the risk of alcohol-induced liver disease in adulthood. Birth Defects Res 2021; 113:451-468. [PMID: 33577143 DOI: 10.1002/bdr2.1881] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 01/13/2021] [Accepted: 01/19/2021] [Indexed: 11/10/2022]
Abstract
Alcohol consumption remains prevalent among pregnant and nursing mothers despite the well-documented adverse effects this may have on the offspring. Moderate-to-high levels of alcohol consumption in pregnancy result in fetal alcohol syndrome (FAS) disorders, with brain defects being chief among the abnormalities. Recent findings indicate that while light-to-moderate levels may not cause FAS, it may contribute to epigenetic changes that make the offspring prone to adverse health outcomes including metabolic disorders and an increased propensity in the adolescent-onset of drinking alcohol. On the one hand, prenatal alcohol exposure (PAE) causes epigenetic changes that affect lipid and glucose transcript regulating genes resulting in metabolic abnormalities. On the other hand, it can program offspring for increased alcohol intake, enhance its palatability, and increase acceptance of alcohol's flavor through associative learning, making alcohol a plausible second hit for the development of alcohol-induced liver disease. Adolescent drinking results in alcohol dependence and abuse in adulthood. Adolescent drinking results in alcohol dependence and abuse in adulthood. Alterations on the opioid system, particularly, the mu-opioid system, has been implicated in the mechanism that induces increased alcohol consumption and acceptance. This review proposes a mechanism that links PAE to the development of alcoholism and eventually to alcoholic liver disease (ALD), which results from prolonged alcohol consumption. While PAE may not lead to ALD development in childhood, there are chances that it may lead to ALD in adulthood.
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Affiliation(s)
- Bernice Asiedu
- Faculty of Health Sciences, School of Physiology, University of the Witwatersrand, Johannesburg, South Africa
| | - Trevor Tapiwa Nyakudya
- Department of Physiology, Faculty of Health Sciences, School of Medicine, University of Pretoria, Gezina, South Africa
| | - Busisani Wiseman Lembede
- Faculty of Health Sciences, School of Physiology, University of the Witwatersrand, Johannesburg, South Africa
| | - Eliton Chivandi
- Faculty of Health Sciences, School of Physiology, University of the Witwatersrand, Johannesburg, South Africa
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24
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Buyco DG, Martin J, Jeon S, Hooks R, Lin C, Carr R. Experimental models of metabolic and alcoholic fatty liver disease. World J Gastroenterol 2021; 27:1-18. [PMID: 33505147 PMCID: PMC7789066 DOI: 10.3748/wjg.v27.i1.1] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 11/01/2020] [Accepted: 12/06/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multi-systemic disease that is considered the hepatic manifestation of metabolic syndrome (MetS). Because alcohol consumption in NAFLD patients is common, there is a significant overlap in the pathogenesis of NAFLD and alcoholic liver disease (ALD). Indeed, MetS also significantly contributes to liver injury in ALD patients. This “syndrome of metabolic and alcoholic steatohepatitis” (SMASH) is thus expected to be a more prevalent presentation in liver patients, as the obesity epidemic continues. Several pre-clinical experimental models that couple alcohol consumption with NAFLD-inducing diet or genetic obesity have been developed to better understand the pathogenic mechanisms of SMASH. These models indicate that concomitant MetS and alcohol contribute to lipid dysregulation, oxidative stress, and the induction of innate immune response. There are significant limitations in the applicability of these models to human disease, such as the ability to induce advanced liver injury or replicate patterns in human food/alcohol consumption. Thus, there remains a need to develop models that accurately replicate patterns of obesogenic diet and alcohol consumption in SMASH patients.
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Affiliation(s)
- Delfin Gerard Buyco
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Jasmin Martin
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Sookyoung Jeon
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Royce Hooks
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Chelsea Lin
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Rotonya Carr
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA 19104, United States
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25
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Tao MH, Fulda KG. Association of Magnesium Intake with Liver Fibrosis among Adults in the United States. Nutrients 2021; 13:E142. [PMID: 33401667 PMCID: PMC7823345 DOI: 10.3390/nu13010142] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 12/21/2020] [Accepted: 12/28/2020] [Indexed: 12/24/2022] Open
Abstract
Liver fibrosis represents the consequences of chronic liver injury. Individuals with alcoholic or nonalcoholic liver diseases are at high risk of magnesium deficiency. This study aimed to evaluate the association between magnesium and calcium intakes and significant liver fibrosis, and whether the associations differ by alcohol drinking status. Based on the National Health and Nutrition Examination Survey (NHANES) 2017-2018, the study included 4166 participants aged >18 years who completed the transient elastography examination and had data available on magnesium intake. The median liver stiffness of 8.2 kPa was used to identify subjects with significant fibrosis (≥F2). The age-adjusted prevalence of significant fibrosis was 12.81%. Overall total magnesium intake was marginally associated with reduced odds of significant fibrosis (p trend = 0.14). The inverse association of total magnesium intake with significant fibrosis was primarily presented among those who had daily calcium intake <1200 mg. There were no clear associations for significant fibrosis with calcium intake. Findings suggest that high total magnesium alone may reduce risk of significant fibrosis. Further studies are needed to confirm these findings.
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Affiliation(s)
- Meng-Hua Tao
- Department of Biostatistics and Epidemiology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Kimberly G. Fulda
- Department of Family Medicine and Osteopathic Manipulative Medicine, NorTex, University of North Texas Health Science Center, Fort Worth, TX 76107, USA;
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26
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Idalsoaga F, Kulkarni AV, Mousa OY, Arrese M, Arab JP. Non-alcoholic Fatty Liver Disease and Alcohol-Related Liver Disease: Two Intertwined Entities. Front Med (Lausanne) 2020; 7:448. [PMID: 32974366 PMCID: PMC7468507 DOI: 10.3389/fmed.2020.00448] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 07/06/2020] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, with a prevalence of 25-30%. Since its first description in 1980, NAFLD has been conceived as a different entity from alcohol-related fatty liver disease (ALD), despite that, both diseases have an overlap in the pathophysiology, share genetic-epigenetic factors, and frequently coexist. Both entities are characterized by a broad spectrum of histological features ranging from isolated steatosis to steatohepatitis and cirrhosis. Distinction between NAFLD and ALD is based on the amount of consumed alcohol, which has been arbitrarily established. In this context, a proposal of positive criteria for NAFLD diagnosis not considering exclusion of alcohol consumption as a prerequisite criterion for diagnosis had emerged, recognizing the possibility of a dual etiology of fatty liver in some individuals. The impact of moderate alcohol use on the severity of NAFLD is ill-defined. Some studies suggest protective effects in moderate doses, but current evidence shows that there is no safe threshold for alcohol consumption for NAFLD. In fact, given the synergistic effect between alcohol consumption, obesity, and metabolic dysfunction, it is likely that alcohol use serves as a significant risk factor for the progression of liver disease in NAFLD and metabolic syndrome. This also affects the incidence of hepatocellular carcinoma. In this review, we summarize the overlapping pathophysiology of NAFLD and ALD, the current data on alcohol consumption in patients with NAFLD, and the effects of metabolic dysfunction and overweight in ALD.
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Affiliation(s)
- Francisco Idalsoaga
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Anand V Kulkarni
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Omar Y Mousa
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States.,Division of Gastroenterology and Hepatology, Mayo Clinic Health System, Mankato, MN, United States
| | - Marco Arrese
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.,Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan Pablo Arab
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.,Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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27
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Ntandja Wandji LC, Gnemmi V, Mathurin P, Louvet A. Combined alcoholic and non-alcoholic steatohepatitis. JHEP Rep 2020; 2:100101. [PMID: 32514497 PMCID: PMC7267467 DOI: 10.1016/j.jhepr.2020.100101] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 02/18/2020] [Accepted: 03/10/2020] [Indexed: 02/06/2023] Open
Abstract
While metabolic syndrome and alcohol consumption are the two main causes of chronic liver disease, one of the two conditions is often predominant, with the other acting as a cofactor of morbimortality. It has been shown that obesity and alcohol act synergistically to increase the risk of fibrosis progression, hepatic carcinogenesis and mortality, while genetic polymorphisms can strongly influence disease progression. Based on common pathogenic pathways, there are several potential targets that could be used to treat both diseases; based on the prevalence and incidence of these diseases, new therapies and clinical trials are needed urgently.
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Key Words
- ACC, acetyl-CoA carboxylase
- ALD
- ALD, alcohol-related liver disease
- ASH
- ASH, alcohol-related steatohepatitis
- ASK-1, apoptosis signal-regulating kinase 1
- Alcohol
- BMI, body mass index
- CLD, chronic liver disease
- CPT, carnitine palmitoyltransferase
- DNL, de novo lipogenesis
- EASL, European Association for the Study of the Liver
- ER, endoplasmic reticulum
- FXR, farnesoid X receptor
- HCC, hepatocellular carcinoma
- HSD17B13, hydroxysteroid 17-beta dehydrogenase 13
- IL, interleukin
- LPS, lipopolysaccharide
- MBOAT7, membrane bound O-acyl transferase 7
- MELD, model for end-stage liver disease
- NAFLD
- NAFLD, non-alcoholic fatty liver disease
- NASH
- NASH, non-alcoholic steatohepatitis
- OR, odds ratio
- PAMP, pathogen-associated molecular pattern
- PI3K, phosphatidylinositol-3-kinase
- PIP3, phosphatidylinositol 3,4,5-triphosphate
- PNPLA3, palatin-like phospholipase domain-containing 3
- PRKCE, protein kinase C Epsilon
- ROS, reactive oxygen species
- SREBP-1c, sterol regulatory element binding protein-1c
- TLR, Toll-like receptor
- TM6SF2, transmembrane 6 superfamily member 2
- TNF-α, tumour necrosis factor-α
- WHO, World Health Organization
- diabetes
- metabolic syndrome
- obesity
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Affiliation(s)
- Line Carolle Ntandja Wandji
- Service des maladies de l'appareil digestif, Hôpital Huriez, Rue Polonowski, 59037 Lille Cedex, France
- Université Lille Nord de France, Lille, France
- Unité INSERM 995, Lille, France
| | | | - Philippe Mathurin
- Service des maladies de l'appareil digestif, Hôpital Huriez, Rue Polonowski, 59037 Lille Cedex, France
- Université Lille Nord de France, Lille, France
- Unité INSERM 995, Lille, France
| | - Alexandre Louvet
- Service des maladies de l'appareil digestif, Hôpital Huriez, Rue Polonowski, 59037 Lille Cedex, France
- Université Lille Nord de France, Lille, France
- Unité INSERM 995, Lille, France
- Corresponding author. Address: Service des maladies de l'appareil digestif, Hôpital Huriez, Rue Polonowski, 59037 Lille Cedex, France. Tel.: +33 320445597; fax: +33 320445564.
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28
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Li YY, Zhong YJ, Cheng Q, Wang YZ, Fan YY, Yang CF, Ma Z, Li YW, Li L. miR-378b Regulates Insulin Sensitivity by Targeting Insulin Receptor and p110α in Alcohol-Induced Hepatic Steatosis. Front Pharmacol 2020; 11:717. [PMID: 32508647 PMCID: PMC7251170 DOI: 10.3389/fphar.2020.00717] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 04/30/2020] [Indexed: 12/12/2022] Open
Abstract
Insulin resistance has been implicated in alcoholic liver disease. A previous study has shown that microRNAs (miRNAs) play a major role in the production, secretion, and function of insulin. MiRNAs are capable of repressing multiple target genes that in turn negatively regulate various physiological and pathological activities. However, current information on the biological function of miRNAs in insulin resistance is limited. The goal of the present study was to elucidate the role of miR-378b in alcohol-induced hepatic insulin resistance and its underlying mechanism. This study has observed that miR-378b is up-regulated in National Institute on Alcohol Abuse and Alcoholism (NIAAA) alcoholic mouse models as well as in ethanol-induced L-02 cells in vitro. Furthermore, miR-378b overexpression impaired the insulin signaling pathway, and inhibition of miR-378b improved insulin sensitivity in vivo and in vitro. A mechanistic study revealed that IR and p110α are direct targets of miR-378b. Together, these results suggest that miR-378b controls insulin sensitivity by targeting the insulin receptor (IR) as well as p110α and possibly play an inhibitory role in the development of insulin resistance, thereby providing insights into the development of novel diagnostic and treatment methods.
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Affiliation(s)
- Yuan-yuan Li
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Yu-juan Zhong
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Qi Cheng
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Ying-zhao Wang
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Yuan-yuan Fan
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Cheng-fang Yang
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Zuheng Ma
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Yong-wen Li
- College of Pharmacy, Guilin Medical University, Guilin, China
- Center for Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin, China
| | - Li Li
- College of Pharmacy, Guilin Medical University, Guilin, China
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29
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Correnti J, Lin C, Brettschneider J, Kuriakose A, Jeon S, Scorletti E, Oranu A, McIver-Jenkins D, Kaneza I, Buyco D, Saiman Y, Furth EE, Argemi J, Bataller R, Holland WL, Carr RM. Liver-specific ceramide reduction alleviates steatosis and insulin resistance in alcohol-fed mice. J Lipid Res 2020; 61:983-994. [PMID: 32398264 PMCID: PMC7328039 DOI: 10.1194/jlr.ra119000446] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 04/29/2020] [Indexed: 12/20/2022] Open
Abstract
Alcohol's impairment of both hepatic lipid metabolism and insulin resistance (IR) are key drivers of alcoholic steatosis, the initial stage of alcoholic liver disease (ALD). Pharmacologic reduction of lipotoxic ceramide prevents alcoholic steatosis and glucose intolerance in mice, but potential off-target effects limit its strategic utility. Here, we employed a hepatic-specific acid ceramidase (ASAH) overexpression model to reduce hepatic ceramides in a Lieber-DeCarli model of experimental alcoholic steatosis. We examined effects of alcohol on hepatic lipid metabolism, body composition, energy homeostasis, and insulin sensitivity as measured by hyperinsulinemic-euglycemic clamp. Our results demonstrate that hepatic ceramide reduction ameliorates the effects of alcohol on hepatic lipid droplet (LD) accumulation by promoting VLDL secretion and lipophagy, the latter of which involves ceramide cross-talk between the lysosomal and LD compartments. We additionally demonstrate that hepatic ceramide reduction prevents alcohol's inhibition of hepatic insulin signaling. These effects on the liver are associated with a reduction in oxidative stress markers and are relevant to humans, as we observe peri- LD ASAH expression in human ALD. Together, our results suggest a potential role for hepatic ceramide inhibition in preventing ALD.
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Affiliation(s)
- Jason Correnti
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA
| | - Chelsea Lin
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA
| | | | - Amy Kuriakose
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA
| | - Sookyoung Jeon
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA
| | - Eleonora Scorletti
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA
| | - Amanke Oranu
- Division of Gastroenterology, United Health Services, Binghamton, NY
| | - Dru McIver-Jenkins
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA
| | - Isabelle Kaneza
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA
| | - Delfin Buyco
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA
| | - Yedidya Saiman
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA
| | - Emma E Furth
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
| | - Josepmaria Argemi
- Center for Liver Diseases, Pittsburgh Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Ramon Bataller
- Center for Liver Diseases, Pittsburgh Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - William L Holland
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT
| | - Rotonya M Carr
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA. mailto:
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30
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Gopal T, Kumar N, Perriotte-Olson C, Casey CA, Donohue TM, Harris EN, Talmon G, Kabanov AV, Saraswathi V. Nanoformulated SOD1 ameliorates the combined NASH and alcohol-associated liver disease partly via regulating CYP2E1 expression in adipose tissue and liver. Am J Physiol Gastrointest Liver Physiol 2020; 318:G428-G438. [PMID: 31928222 PMCID: PMC7099493 DOI: 10.1152/ajpgi.00217.2019] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Enhanced free fatty acid (FFA) flux from adipose tissue (AT) to liver plays an important role in the development of nonalcoholic steatohepatitis (NASH) and alcohol-associated liver disease (AALD). We determined the effectiveness of nanoformulated superoxide dismutase 1 (Nano) in attenuating liver injury in a mouse model exhibiting a combination of NASH and AALD. Male C57BL6/J mice were fed a chow diet (CD) or a high-fat diet (HF) for 10 wk followed by pair feeding of the Lieber-DeCarli control (control) or ethanol (ET) diet for 4 wk. Nano was administered once every other day for the last 2 wk of ET feeding. Mice were divided into 1) CD + control diet (CD + Cont), 2) high-fat diet (HF) + control diet (HF + Cont), 3) HF + Cont + Nano, 4) HF + ET diet (HF + ET), and 5) HF + ET + Nano. The total fat mass, visceral AT mass (VAT), and VAT perilipin 1 content were significantly lower only in HF + ET-fed mice but not in HF + ET + Nano-treated mice compared with controls. The HF + ET-fed mice showed an upregulation of VAT CYP2E1 protein, and Nano abrogated this effect. We noted a significant rise in plasma FFAs, ALT, and monocyte chemoattractant protein-1 in HF + ET-fed mice, which was blunted in HF + ET + Nano-treated mice. HF + ET-induced increases in hepatic steatosis and inflammatory markers were attenuated upon Nano treatment. Nano reduced hepatic CYP2E1 and enhanced catalase levels in HF + ET-fed mice with a concomitant increase in SOD1 protein and activity in liver. Nano was effective in attenuating AT and liver injury in mice exhibiting a combination of NASH and AALD, partly via reduced CYP2E1-mediated ET metabolism in these organs.NEW & NOTEWORTHY Increased free fatty acid flux from adipose tissue (AT) to liver accompanied by oxidative stress promotes nonalcoholic steatohepatitis (NASH) and alcohol-associated liver injury (AALD). Obesity increases the severity of AALD. Using a two-hit model involving a high-fat diet and chronic ethanol feeding to mice, and treating them with nanoformulated superoxide dismutase (nanoSOD), we have shown that nanoSOD improves AT lipid storage, reduces CYP2E1 in AT and liver, and attenuates the combined NASH/AALD in mice.
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Affiliation(s)
- Thiyagarajan Gopal
- 1Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Narendra Kumar
- 1Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Curtis Perriotte-Olson
- 1Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Carol A. Casey
- 2Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska,3Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Terrence M. Donohue
- 2Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska,3Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Edward N. Harris
- 4Department of Biochemistry, University of Nebraska Lincoln, Lincoln, Nebraska
| | - Geoffrey Talmon
- 5Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Alexander V. Kabanov
- 6Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina
| | - Viswanathan Saraswathi
- 1Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska,3Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
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31
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Jeon S, Carr R. Alcohol effects on hepatic lipid metabolism. J Lipid Res 2020; 61:470-479. [PMID: 32029510 DOI: 10.1194/jlr.r119000547] [Citation(s) in RCA: 175] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 01/28/2020] [Indexed: 12/16/2022] Open
Abstract
Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease with significant morbidity and mortality worldwide. ALD begins with simple hepatic steatosis and progresses to alcoholic steatohepatitis, fibrosis, and cirrhosis. The severity of hepatic steatosis is highly associated with the development of later stages of ALD. This review explores the disturbances of alcohol-induced hepatic lipid metabolism through altered hepatic lipid uptake, de novo lipid synthesis, fatty acid oxidation, hepatic lipid export, and lipid droplet formation and catabolism. In addition, we review emerging data on the contributions of genetics and bioactive lipid metabolism in alcohol-induced hepatic lipid accumulation.
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Affiliation(s)
- Sookyoung Jeon
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA
| | - Rotonya Carr
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA
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Lanng AR, Gasbjerg LS, Bergmann NC, Bergmann S, Helsted MM, Gillum MP, Hartmann B, Holst JJ, Vilsbøll T, Knop FK. Gluco-metabolic effects of oral and intravenous alcohol administration in men. Endocr Connect 2019; 8:1372-1382. [PMID: 31518994 PMCID: PMC6790903 DOI: 10.1530/ec-19-0317] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 09/13/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Ingestion of the calorically dense compound alcohol may cause metabolic disturbances including hypoglycaemia, hepatic steatosis and insulin resistance, but the underlying mechanisms are uncertain. The gastrointestinal tract is well recognised as a major influencer on glucose, protein and lipid metabolism, but its role in alcohol metabolism remains unclear. OBJECTIVE To examine the effects of oral and intravenous alcohol, respectively, on plasma concentrations of several gluco-regulatory hormones including serum/plasma insulin, C-peptide, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF21). DESIGN AND METHODS In a double-blinded, randomised, crossover design, we subjected 12 healthy men to intragastric ethanol infusion (IGEI) and an isoethanolaemic intravenous ethanol infusion (IVEI) (0.7 g alcohol per kg body weight), respectively, on two separate experimental days. RESULTS Isoethanolaemia during the two alcohol administration forms was obtained (P = 0.38). During both interventions, plasma glucose peaked after ~30 min and thereafter fell below baseline concentrations. GIP and GLP-1 concentrations were unaffected by the two interventions. Insulin concentrations were unaffected by IGEI but decreased during IVEI. C-peptide, insulin secretion rate and glucagon concentrations were lowered similarly during IGEI and IVEI. FGF21 concentrations increased dramatically (nine-fold) and similarly during IGEI and IVEI. CONCLUSIONS Alcohol does not seem to affect the secretion of incretin hormones but decreased insulin and glucagon secretion independently of gut-derived factors. IGEI as well as IVEI potently stimulate FGF21 secretion indicating a gut-independent effect of alcohol on FGF21 secretion in humans.
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Affiliation(s)
- Amalie R Lanng
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Lærke S Gasbjerg
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Natasha C Bergmann
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Sigrid Bergmann
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Mads M Helsted
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Matthew P Gillum
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Correspondence should be addressed to F K Knop:
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Cheng Q, Li YW, Yang CF, Zhong YJ, Li L. Ethanol-Induced Hepatic Insulin Resistance is Ameliorated by Methyl Ferulic Acid Through the PI3K/AKT Signaling Pathway. Front Pharmacol 2019; 10:949. [PMID: 31555134 PMCID: PMC6726842 DOI: 10.3389/fphar.2019.00949] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 07/25/2019] [Indexed: 12/13/2022] Open
Abstract
One of the key events during the development of alcoholic liver disease (ALD) is that alcohol inhibits the insulin signaling pathway in liver and leads to disorders of glucose and lipid metabolism. Methyl ferulic acid (MFA) is a biologically active monomer isolated from the root of Securidaca inappendiculata Hasskarl. It has been reported that MFA has a hepatoprotective effect against alcohol-induced liver injury in vivo and in vitro. However, the effect of MFA on ethanol-induced insulin resistance in ALD remains unclear. In this study, we investigated whether MFA could exert protective effects against hepatic insulin resistance in ethanol-induced L-02 cells and ALD rats. ALD was induced in vivo by feeding Lieber-DeCarli diet containing 5% (w/v) alcohol for 16 weeks to Sprague-Dawley rats. Insulin resistance was induced in vitro in human hepatocyte L-02 cells with 200 mM ethanol for 24 h followed by 10-7 nM insulin for 30 min. MFA exhibited the effects of inhibited insulin resistance, reduced enzymatic capacity for hepatic gluconeogenesis, and increased hepatic glycogen synthesis both in vivo and in vitro. In addition, the results of transcriptome sequencing of liver tissues in the ethanol- and MFA-treated groups indicated that "pyruvate metabolism," "glycolysis/gluconeogenesis," and "fatty acid metabolism" were significantly different between ethanol- and MFA-treated groups. Further studies suggested that MFA activated the hepatic phosphatidylinositol 3-kinase (PI3K)/AKT pathway in vivo and in vitro. Taken together, these findings suggested that MFA effectively ameliorated hepatic insulin resistance in ALD at least partially by acting on the PI3K/AKT pathway.
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Affiliation(s)
- Qi Cheng
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Yong Wen Li
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Cheng Fang Yang
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Yu Juan Zhong
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Li Li
- College of Pharmacy, Guilin Medical University, Guilin, China
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Park KH, Kim SH. Low dose of chronic ethanol exposure in adult zebrafish induces hepatic steatosis and injury. Biomed Pharmacother 2019; 117:109179. [PMID: 31387182 DOI: 10.1016/j.biopha.2019.109179] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 06/26/2019] [Accepted: 06/26/2019] [Indexed: 12/20/2022] Open
Abstract
Chronic alcohol consumption is a major cause of chronic liver disease worldwide. Adult zebrafish have emerged as a new vertebrate model of alcoholic liver disease. In previous research, a high dose of chronic ethanol treatment induced characteristic features of steatosis and hepatic injury in adult zebrafish, yet the ethanol concentration in that study was significantly higher than the lethal dose in humans. In the current study, we examined whether a low dose of chronic ethanol exposure in adult zebrafish induced the metabolic and pathological features seen in alcoholic liver disease. We found that chronic ethanol treatment at 0.2% ethanol (v/v) concentration for 4 weeks induced a significant elevation of serum glucose and triacylglycerol in adult zebrafish. In addition, serum alanine aminotransferase activity was significantly elevated after ethanol treatment. Histological analysis revealed steatosis and hepatocyte ballooning phenotype. Gene expression analysis using quantitative real-time PCR suggested that ethanol treatment induced inflammation, apoptosis, and fibrosis. In addition, we found significant increases in gene expression involved in glucose and lipid metabolism as well as mitochondrial biogenesis and function. Importantly, expression of genes involved in oxidative and endoplasmic reticulum stress, two major stress signaling pathways underlying hepatic injury in alcoholic liver disease, were highly upregulated in the livers of adult zebrafish after chronic ethanol treatment. In conclusion, we found that 4 weeks of low dose ethanol exposure leads to typical ethanol-induced liver disease, with pathological and gene expression patterns.
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Affiliation(s)
- Ki-Hoon Park
- Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Seok-Hyung Kim
- Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, 29425, USA.
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Schwarzenberg SJ, Uc A, Zimmerman B, Wilschanski M, Wilcox CM, Whitcomb DC, Werlin SL, Troendle D, Tang G, Slivka A, Singh VK, Sherman S, Shah U, Sandhu BS, Romagnuolo J, Rhee S, Pohl JF, Perito ER, Ooi CY, Nathan JD, Muniraj T, Morinville VD, McFerron B, Mascarenhas M, Maqbool A, Liu Q, Lin TK, Lewis M, Husain SZ, Himes R, Heyman MB, Guda N, Gonska T, Giefer MJ, Gelrud A, Gariepy CE, Gardner TB, Freedman SD, Forsmark CE, Fishman DS, Cote GA, Conwell D, Brand RE, Bellin M, Barth B, Banks PA, Anderson MA, Amann ST, Alkaade S, Abu-El-Haija M, Abberbock JN, Lowe ME, Yadav D. Chronic Pancreatitis: Pediatric and Adult Cohorts Show Similarities in Disease Progress Despite Different Risk Factors. J Pediatr Gastroenterol Nutr 2019; 68:566-573. [PMID: 30897605 PMCID: PMC6492264 DOI: 10.1097/mpg.0000000000002279] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVES The aim of the present study was to investigate the natural history of chronic pancreatitis (CP); patients in the North American Pancreatitis Study2 (NAPS2, adults) and INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE, pediatric) were compared. METHODS Demographics, risk factors, disease duration, management and outcomes of 224 children and 1063 adults were compared using appropriate statistical tests for categorical and continuous variables. RESULTS Alcohol was a risk in 53% of adults and 1% of children (P < 0.0001); tobacco in 50% of adults and 7% of children (P < 0.0001). Obstructive factors were more common in children (29% vs 19% in adults, P = 0.001). Genetic risk factors were found more often in children. Exocrine pancreatic insufficiency was similar (children 26% vs adult 33%, P = 0.107). Diabetes was more common in adults than children (36% vs 4% respectively, P < 0.0001). Median emergency room visits, hospitalizations, and missed days of work/school were similar across the cohorts. As a secondary analysis, NAPS2 subjects with childhood onset (NAPS2-CO) were compared with INSPPIRE subjects. These 2 cohorts were more similar than the total INSPPIRE and NAPS2 cohorts, including for genetic risk factors. The only risk factor significantly more common in the NAPS2-CO cohort compared with the INSPPIRE cohort was alcohol (9% NAPS2-CO vs 1% INSPPIRE cohorts, P = 0.011). CONCLUSIONS Despite disparity in age of onset, children and adults with CP exhibit similarity in demographics, CP treatment, and pain. Differences between groups in radiographic findings and diabetes prevalence may be related to differences in risk factors associated with disease and length of time of CP.
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Affiliation(s)
| | - Aliye Uc
- University of Iowa, Stead Family Children's Hospital
| | | | | | - C Mel Wilcox
- Department of Medicine, University of Alabama Birmingham, Birmingham, AL
| | - David C Whitcomb
- Department of Medicine
- Department of Cell Biology & Physiology
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA
- Palmetto Health, Columbia Gastroenterology Associates, Columbia, SC
| | | | - David Troendle
- University of Texas Southwestern Medical School, Dallas, TX
| | - Gong Tang
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
| | | | - Vikesh K Singh
- Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Stuart Sherman
- Department of Medicine, Indiana University, Indianapolis, IN
| | - Uzma Shah
- Massachusetts General Hospital for Children, Harvard Medical School, Boston, MA
| | - Bimaljit S Sandhu
- Richmond Gastroenterology Associates, St. Mary's Hospital, Richmond, VA
| | | | - Sue Rhee
- University of California San Francisco Benioff Children's Hospital, San Francisco, CA
| | | | - Emily R Perito
- University of California San Francisco Benioff Children's Hospital, San Francisco, CA
| | - Chee Y Ooi
- School of Women's and Children's Health, Medicine, University of New South Wales and Sydney Children's Hospital Randwick Sydney, Australia
| | - Jaimie D Nathan
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | | | | | - Brian McFerron
- Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN
| | | | - Asim Maqbool
- Children's Hospital of Philadelphia, Philadelphia, PA
| | - Quin Liu
- Cedars-Sinai Medical Center, Los Angeles, CA
| | - Tom K Lin
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Michele Lewis
- Department of Medicine, Mayo Clinic, Jacksonville, FL
| | | | | | - Melvin B Heyman
- University of California San Francisco Benioff Children's Hospital, San Francisco, CA
| | - Nalini Guda
- Aurora Health Care, St. Luke's Medical Center, Milwaukee, WI
| | - Tanja Gonska
- Hospital for Sick Children, Toronto, Ontario, Canada
| | | | | | | | - Timothy B Gardner
- Department of Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH
| | | | - Christopher E Forsmark
- Department of Medicine, University of Florida, Gainesville, FL
- Department of Medicine, Medical University of South Carolina, Charleston, SC
| | | | - Gregory A Cote
- Aurora Health Care, St. Luke's Medical Center, Milwaukee, WI
| | - Darwin Conwell
- Department of Medicine, Ohio State University, Columbus, OH
| | | | - Melena Bellin
- University of Minnesota Masonic Children's Hospital, Minneapolis, MN
| | - Bradley Barth
- University of Texas Southwestern Medical School, Dallas, TX
| | - Peter A Banks
- Department of Medicine, Brigham and Women's Hospital, Boston, MA
| | | | | | - Samer Alkaade
- Department of Medicine, Saint Louis University, St. Louis, MO
| | | | - Judah N Abberbock
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
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Hepatoprotective activity of metformin: A new mission for an old drug? Eur J Pharmacol 2019; 850:1-7. [PMID: 30753869 DOI: 10.1016/j.ejphar.2019.02.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Revised: 02/02/2019] [Accepted: 02/08/2019] [Indexed: 02/06/2023]
Abstract
Metformin, as a dimethyl biguanide prescribed as the first-line medication for treatment of type 2 diabetes mellitus, is one of the most frequently used drugs, worldwide. However, the beneficial effects of metformin are not limited to insulin sensitizing and blood glucose lowering effects as recent clinical trials deciphered lower cancer risk in metformin users. In addition, metformin protected the liver against chemical or viral hepatotoxicants through various mechanisms including activation of AMPK via inhibition of mitochondrial complex I, inhibition of mitogen activated protein kinase (MAPK) and inhibition of Smads phosphorylation. Clinical trials are under way to assess possible additive effects of metformin when co-administered along with the standard regimen for hepatocellular carcinoma (HCC) treatment. This review outlines the molecular mechanisms behind protective activity of metformin against different liver diseases.
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Nikolova-Karakashian M. Alcoholic and non-alcoholic fatty liver disease: Focus on ceramide. Adv Biol Regul 2018; 70:40-50. [PMID: 30455063 DOI: 10.1016/j.jbior.2018.11.004] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 11/13/2018] [Accepted: 11/13/2018] [Indexed: 12/24/2022]
Abstract
Sphingolipids are class of metabolically distinct lipids that play structural and signaling functions in all organisms. Sphingolipid metabolism is deregulated during various diseases such as cancer, neurological and immune disorders, and metabolic syndrome. With the advancement of sphingo-lipidomics and sphingo-genomics, an understanding of the specific roles of ceramide, the quintessential bioactive sphingolipid, in fatty liver disease has taken shape. Two major pathways for ceramide generation, the de novo pathway and the sphingomyelinase pathway are activated in the course of both, the non-alcoholic and the alcoholic, forms of fatty liver disease. The mechanisms of activation of these two pathways are distinct and reflect the different disease etiology in each case; at the same time, common processes impacted by the resulting ceramide overproduction involve lipotoxocity, ER/mitochondrial stress, inflammation, and de-regulation of hepatic lipid metabolism. Studies in human patients and animal models have delineated specific enzymes and ceramide species that are involved at the different stages of the disease, and represent novel pharmaceutical targets for successful management of fatty liver disease.
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Affiliation(s)
- Mariana Nikolova-Karakashian
- Department of Physiology, University of Kentucky College of Medicine, 800 Rose Str., MS 508, Lexington, KY, 40536, United States.
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El-Kharashi OA, El-Din Aly El-Waseef DA, Nabih ES, Mohamed DI. Targeting NLRP3 inflammasome via acetylsalicylic acid: Role in suppressing hepatic dysfunction and insulin resistance induced by atorvastatin in naïve versus alcoholic liver in rats. Biomed Pharmacother 2018; 107:665-674. [DOI: 10.1016/j.biopha.2018.08.032] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 08/08/2018] [Accepted: 08/09/2018] [Indexed: 12/22/2022] Open
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Ethanol and C2 ceramide activate fatty acid oxidation in human hepatoma cells. Sci Rep 2018; 8:12923. [PMID: 30150688 PMCID: PMC6110824 DOI: 10.1038/s41598-018-31025-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 08/04/2018] [Indexed: 02/07/2023] Open
Abstract
Obesogenic lipids and the sphingolipid ceramide have been implicated as potential cofactors in alcoholic liver disease (ALD) patients. However, the mechanisms by which these lipids modulate lipid trafficking in ethanol-treated human liver cells to promote steatosis, an early stage of ALD, are poorly understood. We measured fatty acid (FA) uptake, triglyceride export, FA synthesis and FA oxidation in human hepatoma (VL-17A) cells in response to ethanol and the exogenous lipids oleate, palmitate and C2 ceramide. We found that in combination with ethanol, both oleate and palmitate promote lipid droplet accumulation while C2 ceramide inhibits lipid droplet accumulation by enhancing FA oxidation. Further, using both a pharmacologic and siRNA approach to reduce peroxisome proliferator-activated receptors α (PPARα) gene expression, we demonstrate that C2 ceramide abrogates ethanol-mediated suppression of FA oxidation through an indirect PPARα mechanism. Together, these data suggest that lipids interact differentially with ethanol to modulate hepatocellular lipid droplet accumulation and may provide novel targets for preventing the earliest stage of alcoholic liver disease, alcoholic steatosis.
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Pickett-Blakely O, Young K, Carr RM. Micronutrients in Nonalcoholic Fatty Liver Disease Pathogenesis. Cell Mol Gastroenterol Hepatol 2018; 6:451-462. [PMID: 30294653 PMCID: PMC6170520 DOI: 10.1016/j.jcmgh.2018.07.004] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 07/19/2018] [Indexed: 02/06/2023]
Abstract
Micronutrients include electrolytes, minerals, vitamins, and carotenoids, and are required in microgram or milligram quantities for cellular metabolism. The liver plays an important role in micronutrient metabolism and this metabolism often is altered in chronic liver diseases. Here, we review how the liver contributes to micronutrient metabolism; how impaired micronutrient metabolism may be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a systemic disorder of energy, glucose, and lipid homeostasis; and how insights gained from micronutrient biology have informed NAFLD therapeutics. Finally, we highlight some of the challenges and opportunities that remain with investigating the contribution of micronutrients to NAFLD pathology and suggest strategies to incorporate our understanding into the care of NAFLD patients.
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Affiliation(s)
| | | | - Rotonya M. Carr
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania
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Magnesium intake and mortality due to liver diseases: Results from the Third National Health and Nutrition Examination Survey Cohort. Sci Rep 2017; 7:17913. [PMID: 29263344 PMCID: PMC5738415 DOI: 10.1038/s41598-017-18076-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 12/05/2017] [Indexed: 12/15/2022] Open
Abstract
People with fatty liver disease are at high risk of magnesium deficiency. Meanwhile, low magnesium status is linked to both chronic inflammation and insulin resistance. However, no study has investigated the association between intake of magnesium and risk of mortality due to liver diseases. We evaluated the association between total magnesium intake and mortality due to liver diseases in the Third National Health and Nutrition Examination Study (NHANES III) cohort, which included 13,504 participants who completed liver ultrasound examination for hepatic steatosis. Overall magnesium intake was associated with a reduced risk of mortality due to liver disease at borderline significance (P = 0.05). In fully-adjusted analyses, every 100 mg increase in intake of magnesium was associated with a 49% reduction in the risk for mortality due to liver diseases. Although interactions between magnesium intake and alcohol use and hepatic steatosis at baseline were not significant (P > 0.05), inverse associations between magnesium intake and liver disease mortality were stronger among alcohol drinkers and those with hepatic steatosis. Our findings suggest higher intakes of magnesium may be associated with a reduced risk of mortality due to liver disease particularly among alcohol drinkers and those with hepatic steatosis. Further studies are warranted to confirm the findings.
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Greuter T, Malhi H, Gores GJ, Shah VH. Therapeutic opportunities for alcoholic steatohepatitis and nonalcoholic steatohepatitis: exploiting similarities and differences in pathogenesis. JCI Insight 2017; 2:95354. [PMID: 28878132 DOI: 10.1172/jci.insight.95354] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are among the most frequent causes of chronic liver disease in the United States. Although the two entities are triggered by different etiologies - chronic alcohol consumption (ASH) and obesity-associated lipotoxicity (NASH) - they share overlapping histological and clinical features owing to common pathogenic mechanisms. These pathogenic processes include altered hepatocyte lipid metabolism, organelle dysfunction (i.e., ER stress), hepatocyte apoptosis, innate immune system activation, and hepatic stellate cell activation. Nonetheless, there are several disease-specific molecular signaling pathways, such as differential pathway activation downstream of TLR4 (MyD88-dependence in NASH versus MyD88-independence in ASH), inflammasome activation and IL-1β signaling in ASH, insulin resistance and lipotoxicity in NASH, and dysregulation of different microRNAs, which clearly highlight that ASH and NASH are two distinct biological entities. Both pathogenic similarities and differences have therapeutic implications. In this Review, we discuss these pathogenic mechanisms and their therapeutic implications for each disease, focusing on both shared and distinct targets.
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Affiliation(s)
- Thomas Greuter
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.,Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Harmeet Malhi
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Gregory J Gores
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Vijay H Shah
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Williams B, Correnti J, Oranu A, Lin A, Scott V, Annoh M, Beck J, Furth E, Mitchell V, Senkal CE, Obeid L, Carr RM. A novel role for ceramide synthase 6 in mouse and human alcoholic steatosis. FASEB J 2017; 32:130-142. [PMID: 28864659 DOI: 10.1096/fj.201601142r] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 08/21/2017] [Indexed: 12/19/2022]
Abstract
Perilipin 2 (PLIN2) is a lipid-droplet protein that is up-regulated in alcoholic steatosis and associated with hepatic accumulation of ceramides, bioactive lipids implicated in alcoholic liver disease pathogenesis. The specific role of ceramide synthetic enzymes in the regulation of PLIN2 and promotion of hepatocellular lipid accumulation is not well understood. We examined the effects of pharmacologic ceramide synthesis inhibition on hepatic PLIN2 expression, steatosis, and glucose and lipid homeostasis in mice with alcoholic steatosis and in ethanol-incubated human hepatoma VL17A cells. In cells, pharmacologic inhibition of ceramide synthase reduced lipid accumulation by reducing PLIN2 RNA stability. The subtype ceramide synthase (CerS)6 was specifically up-regulated in experimental alcoholic steatosis in vivo and in vitro and was up-regulated in zone 3 hepatocytes in human alcoholic steatosis. In vivo ceramide reduction by inhibition of de novo ceramide synthesis reduced PLIN2 and hepatic steatosis in alcohol-fed mice, but only de novo synthesis inhibition, not sphingomyelin hydrolysis, improved glucose tolerance and dyslipidemia. These findings implicate CerS6 as a novel regulator of PLIN2 and suggest that ceramide synthetic enzymes may promote the earliest stage of alcoholic liver disease, alcoholic steatosis.-Williams, B., Correnti, J., Oranu, A., Lin, A., Scott, V., Annoh, M., Beck, J., Furth, E., Mitchell, V., Senkal, C. E., Obeid, L., Carr, R. M. A novel role for ceramide synthase 6 in mouse and human alcoholic steatosis.
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Affiliation(s)
- Bianca Williams
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Jason Correnti
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Amanke Oranu
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Annie Lin
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Victoria Scott
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Maxine Annoh
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - James Beck
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Emma Furth
- Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Victoria Mitchell
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Can E Senkal
- Department of Medicine, Stony Brook University School of Medicine, Stony Brook, New York, USA; and
| | - Lina Obeid
- Department of Medicine, Stony Brook University School of Medicine, Stony Brook, New York, USA; and.,Northport Veterans Affairs Medical Center, Northport, New York, USA
| | - Rotonya M Carr
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA;
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Circulating fibroblast growth factor 21 in patients with liver cirrhosis. Clin Exp Med 2017; 18:63-69. [DOI: 10.1007/s10238-017-0468-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Accepted: 07/10/2017] [Indexed: 12/21/2022]
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Dietary fructose augments ethanol-induced liver pathology. J Nutr Biochem 2017; 43:141-150. [PMID: 28315617 DOI: 10.1016/j.jnutbio.2017.02.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 12/22/2016] [Accepted: 02/08/2017] [Indexed: 12/13/2022]
Abstract
Certain dietary components when combined with alcohol exacerbate alcohol-induced liver injury (ALI). Here, we tested whether fructose, a major ingredient of the western diet, enhances the severity of ALI. We fed mice ethanol for 8 weeks in the following Lieber-DeCarli diets: (a) Regular (contains olive oil); (b) corn oil (contains corn oil); (c) fructose (contains fructose and olive oil) and (d) corn+fructose (contains fructose and corn oil). We compared indices of metabolic function and liver pathology among the different groups. Mice fed fructose-free and fructose-containing ethanol diets exhibited similar levels of blood alcohol, blood glucose and signs of disrupted hepatic insulin signaling. However, only mice given fructose-ethanol diets showed lower insulin levels than their respective controls. Compared with their respective pair-fed controls, all ethanol-fed mice exhibited elevated levels of serum ALT; the inflammatory cytokines TNF-α, MCP-1 and MIP-2; hepatic lipid peroxides and triglycerides. All the latter parameters were significantly higher in mice given fructose-ethanol diets than those fed fructose-free ethanol diets. Mice given fructose-free or fructose-containing ethanol diets each had higher levels of hepatic lipogenic enzymes than controls. However, the level of the lipogenic enzyme fatty acid synthase (FAS) was significantly higher in livers of mice given fructose control and fructose-ethanol diets than in all other groups. Our findings indicate that dietary fructose exacerbates ethanol-induced steatosis, oxidant stress, inflammation and liver injury, irrespective of the dietary fat source, to suggest that inclusion of fructose in or along with alcoholic beverages increases the risk of more severe ALI in heavy drinkers.
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Song M, Chen T, Prough RA, Cave MC, McClain CJ. Chronic Alcohol Consumption Causes Liver Injury in High-Fructose-Fed Male Mice Through Enhanced Hepatic Inflammatory Response. Alcohol Clin Exp Res 2016; 40:518-28. [PMID: 26858005 DOI: 10.1111/acer.12994] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 12/22/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Obesity and the metabolic syndrome occur in approximately one-third of patients with alcoholic liver disease (ALD). The increased consumption of fructose parallels the increased prevalence of obesity and the metabolic syndrome in the United States and worldwide. In this study, we investigated whether dietary high fructose potentiates chronic alcohol-induced liver injury, and explored potential mechanism(s). METHODS Six-week-old male C57BL/6J mice were assigned to 4 groups: control, high fructose, chronic ethanol (EtOH), and high fructose plus chronic alcohol. The mice were fed either control diet or high-fructose diet (60%, w/w) for 18 weeks. Chronic alcohol-fed mice were given 20% (v/v) ethanol (Meadows-Cook model) ad libitum as the only available liquid from the 9th week through the 18th week. Liver injury, steatosis, hepatic inflammatory gene expression, and copper status were assessed. RESULTS High-fructose diet and chronic alcohol consumption alone each induce hepatic fat accumulation and impair copper status. However, the combination of dietary high fructose plus chronic alcohol synergistically induced liver injury as evidenced by robustly increased plasma alanine aminotransferase and aspartate aminotransferase, but the combination did not exacerbate hepatic fat accumulation nor worsen copper status. Moreover, FE-fed mice were characterized by prominent microvesicular steatosis. High-fructose diet and chronic alcohol ingestion together led to a significant up-regulation of Kupffer cell (KC) M1 phenotype gene expression (e.g., tumor necrosis factor-α and monocyte chemoattractant protein-1), as well as Toll-like receptor 4 (TLR4) signaling gene expression, which is also associated with the up-regulation of KCs and activation marker gene expression, including Emr1, CD68, and CD163. CONCLUSIONS Our data suggest that dietary high fructose may potentiate chronic alcohol consumption-induced liver injury. The underlying mechanism might be due to the synergistic effect of dietary high fructose and alcohol on the activation of the TLR4 signaling pathway, which in turn leads to KC activation and phenotype switch toward M1 polarization. This study suggests that alcohol-fructose combination contributes to ALD progression.
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Affiliation(s)
- Ming Song
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
| | - Theresa Chen
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky
| | - Russell A Prough
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, Kentucky
| | - Matthew C Cave
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky.,Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky.,Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, Kentucky.,Robley Rex Louisville Veterans Affairs Medical Center, Louisville, Kentucky
| | - Craig J McClain
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky.,Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky.,Robley Rex Louisville Veterans Affairs Medical Center, Louisville, Kentucky
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Betulin alleviated ethanol-induced alcoholic liver injury via SIRT1/AMPK signaling pathway. Pharmacol Res 2016; 105:1-12. [PMID: 26776965 DOI: 10.1016/j.phrs.2015.12.022] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Revised: 12/19/2015] [Accepted: 12/19/2015] [Indexed: 01/30/2023]
Abstract
The present study was conducted to investigate the protective effect of betulin, a triterpene from the bark of Betula platyphylla Suk, against ethanol-induced alcoholic liver injury and its possible underlying mechanisms. In vitro, human hepatic stellate cell line, LX-2 cells were treated with betulin (6.25, 12.5 and 25 μM) prior to ethanol (50mM) for 24h. Cell viability was analyzed by methyl thiazolyl tetrazolium assay, protein expressions were assessed by Western blot. In vivo, we induced alcoholic liver injury in male C57BL/6 mice, placing them on Lieber-DeCarli ethanol-containing diets for 10 days and then administering a single dose of ethanol (5 g/kg body weight) via gavage. Betulin (20 and 50mg/kg) were given by gavage every day. In vitro results showed that betulin effectively decreased LX-2 cell viability, attenuated collagen-I, α-smooth muscle actin (α-SMA) levels, activated liver kinase B-1 (LKB1) and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Betulin suppressed the expression of sterol regulatory element-binding protein-1 (SREBP-1), and genetic deletion of AMPK blocked the effect of betulin on SREBP-1 in ethanol treated LX-2 cells. In vivo, betulin attenuated the increases in serum aminotransferase and triglyceride levels in the mice fed with chronic-binge ethanol, while significantly inhibited SREBP-1 expression and activated LKB1-AMPK phosphorylation. Additionally, betulin enhanced the sirtuin 1 (SIRT1) expression mediated by ethanol. Taken together, betulin alleviates alcoholic liver injury possibly through blocking the regulation of SREBP-1 on fatty acid synthesis and activating SIRT1-LKB1-AMPK signaling pathway.
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