microRNA-122 regulates hypoxia-inducible factor-1 and vimentin in hepatocytes and correlates with fibrosis in diet-induced steatohepatitis
Department of Medicine, Division of Gastroenterology
Digestive System Diseases | Gastroenterology | Genomics | Hepatology
BACKGROUND and AIMS: miR-122 is the most abundant miRNA in the liver particularly in hepatocytes where it targets cholesterol metabolism. Steatosis, a key component of non-alcoholic fatty liver disease, is regulated by hypoxia-inducible factor-1alpha (HIF-1alpha). Here, we hypothesized that reduced miR-122 has a pathogenic role in steatohepatitis.
METHODS: miR-122 and its target genes were evaluated in mouse livers and/or isolated hepatocytes after methionine-choline-deficient (MCD) or methionine-choline-supplemented (MCS) diet.
RESULTS: Liver and hepatocyte miR-122 expression was significantly decreased in steatohepatitis. A maximum reduction in miR-122 occurred at the fibrosis stage (8 weeks of MCD diet). MAP3K3, a miR-122 target gene, was induced at all stages of non-alcoholic steatohepatitis (NASH; 3-8 weeks) only at the mRNA level. Increased NF-kappaB activation was found in MCD diet-fed mice and MAP3K3 regulated the NF-kappaB DNA binding in naive hepatocytes. HIF-1alpha mRNA and DNA binding and expression of the HIF-1alpha target gene, profibrotic lysyl oxidase, was increased in advanced steatohepatitis (8 weeks). In addition, increase in vimentin and Sirius red staining (liver fibrosis) was found at 8 weeks of MCD diet. Using miR-122 overexpression and inhibition approaches, we confirmed that HIF-1alpha, vimentin and MAP3K3 are novel miR-122 targets in hepatocytes. We report transcriptional repression of miR-122 in NASH. Decreased liver miR-122 was associated with elevated circulating miR-122 in both exosome-rich and protein-rich serum fractions.
CONCLUSIONS: Our novel data suggest that decreased liver miR-122 contributes to upregulation of modulators of tissue remodelling (HIF-1alpha, vimentin and MAP3K3) and might play a role in NASH-induced liver fibrosis.
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Citation: Liver Int. 2014 Jul 10. doi: 10.1111/liv.12633. Link to article on publisher's site
Csak, Timea; Bala, Shashi; Lippai, Dora; Satishchandran, Abhishek; Catalano, Donna; Kodys, Karen; and Szabo, Gyongyi, "microRNA-122 regulates hypoxia-inducible factor-1 and vimentin in hepatocytes and correlates with fibrosis in diet-induced steatohepatitis" (2014). Gastroenterology Publications and Presentations. 128.