Abstract
Background:
Optimal treatment for nonalcoholic steatohepatitis (NASH) has not yet been established, particularly for individuals without diabetes. We examined the effects of metformin, commonly used to treat patients with type 2 diabetes, on liver pathology in a non-diabetic NASH mouse model.
Methodology/principal findings:
Eight-week-old C57BL/6 mice were fed a methionine- and choline-deficient plus high fat (MCD+HF) diet with or without 0.1% metformin for 8 weeks. Co-administration of metformin significantly decreased fasting plasma glucose levels, but did not affect glucose tolerance or peripheral insulin sensitivity. Metformin ameliorated MCD+HF diet-induced hepatic steatosis, inflammation, and fibrosis. Furthermore, metformin significantly reversed hepatic steatosis and inflammation when administered after the development of experimental NASH.
Conclusions/significance:
These histological changes were accompanied by reduced hepatic triglyceride content, suppressed hepatic stellate cell activation, and the downregulation of genes involved in fatty acid metabolism, inflammation, and fibrogenesis. Metformin prevented and reversed steatosis and inflammation of NASH in an experimental non-diabetic model without affecting peripheral insulin resistance.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cluster Analysis
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Disease Models, Animal
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Fatty Liver / drug therapy*
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Fatty Liver / pathology
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Fatty Liver / prevention & control
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Gene Expression Profiling
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Gene Expression Regulation / drug effects
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Gene Regulatory Networks
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Hepatic Stellate Cells / drug effects
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Hepatic Stellate Cells / metabolism
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Hepatitis / drug therapy*
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Hepatitis / pathology
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Hepatitis / prevention & control
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Lipid Metabolism / drug effects
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Liver Cirrhosis / genetics
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Liver Cirrhosis / metabolism
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Liver Cirrhosis / prevention & control
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Metformin / administration & dosage
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Metformin / therapeutic use*
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Mice
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Mice, Inbred NOD
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Non-alcoholic Fatty Liver Disease
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Plasminogen Activator Inhibitor 1 / metabolism
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Signal Transduction / drug effects
Substances
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Plasminogen Activator Inhibitor 1
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Metformin
Grants and funding
This work was supported in part by Grants-in-Aid for Scientific Research (C-23591301 to TT), and a Grant-in-aid for Young Scientists (B-23791022 to HM) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.