Objective miR-21 is an oncomir highly upregulated in hepatocellular carcinoma and in early stages of liver diseases characterised by the presence of steatosis. Whether upregulation of miR-21 contributes to hepatic metabolic disorders and their progression towards cancer is unknown. This study aims at investigating the role of miR-21/miR-21* in early stages of metabolic liver disorders associated with diet-induced obesity (DIO).
Design Constitutive miR-21/miR-21* knockout (miR21KO) and liver-specific miR-21/miR-21* knockout (LImiR21KO) mice were generated. Mice were then fed with high-fat diet (HFD) and alterations of the lipid and glucose metabolism were investigated. Serum and ex vivo explanted liver tissue were analysed.
Results Under normal breeding conditions and standard diet, miR-21/miR-21* deletion in mice was not associated with any detectable phenotypic alterations. However, when mice were challenged with an obesogenic diet, glucose intolerance, steatosis and adiposity were improved in mice lacking miR-21/miR-21*. Deletion of miR-21/miR-21* specifically in hepatocytes led to similar improvements in mice fed an HFD, indicating a crucial role for hepatic miR-21/miR-21* in metabolic disorders associated with DIO. Further molecular analyses demonstrated that miR-21/miR-21* deletion in hepatocytes increases insulin sensitivity and modulates the expression of multiple key metabolic transcription factors involved in fatty acid uptake, de novo lipogenesis, gluconeogenesis and glucose output.
Conclusions Hepatic miR-21/miR-21* deficiency prevents glucose intolerance and steatosis in mice fed an obesogenic diet by altering the expression of several master metabolic regulators. This study points out miR-21/miR-21* as a potential therapeutic target for non-alcoholic fatty liver disease and the metabolic syndrome.
- FATTY LIVER
- GLUCOSE METABOLISM
- LIPID METABOLISM
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NC and PR contributed equally.
Contributors NC and PR: study concept and design; acquisition, analysis and interpretation of data; drafting of the manuscript. CS, CM and MF: acquisition, analysis and interpretation of data. YR, PR, F-PZ and MP: acquisition of data. J-FD and BH: interpretation of data and critical revision of the manuscript for important intellectual content. SN: analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content and obtained funding. MF: study concept and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, obtained funding and study supervision. All authors critically revised the manuscript and approved its ﬁnal version.
Funding This work was supported by the Swiss National Science Foundation (grant N°31003A 119862 and 31003A 135227 to SN and N°310030-152618 and CRSII3-141798 and CRSII3-160717 to MF), The Bo & Kerstin Hjelt Foundation and the EFSD Research Program in Diabetes and Cancer and the Swiss Cancer league (KFS-02502-08-2009) to MF.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.