Difference in expression of hepatic microRNAs miR-29c, miR-34a, miR-155, and miR-200b is associated with strain-specific susceptibility to dietary nonalcoholic steatohepatitis in mice

Abstract

The importance of dysregulation of microRNA (miRNA) expression in nonalcoholic steatohepatitis (NASH) has been increasingly recognized; however, the association between altered expression of miRNAs and pathophysiological features of NASH and whether or not there is a connection between susceptibility to NASH and altered expression of miRNAs are largely unknown. In the present study, male inbred C57BL/6J and DBA/2J mice were fed a lipogenic methyl-deficient diet that causes liver injury similar to human NASH, and the expression of miRNAs and the level of proteins targeted by these miRNAs in the livers were determined. The administration of the methyl-deficient diet triggered NASH-specific changes in the livers of C57BL/6J and DBA/2J mice with a magnitude being more severe in DBA/2J mice. This was evidenced by a greater extent of expression of fibrosis-related genes in the livers of methyl-deficient DBA/2J mice. The development of NASH was accompanied by prominent changes in the expression of miRNAs, including miR-29c, miR-34a, miR-155, and miR-200b. Interestingly, changes in the expression of these miRNAs and protein levels of their targets, including Cebp-β, Socs 1, Zeb-1, and E-cadherin, in the livers of DBA/2J mice fed a methyl-deficient diet were more pronounced as compared to the C57BL/6J mice. These results demonstrate that alterations in expression of miRNAs are a prominent event during development of NASH induced by methyl deficiency and strongly suggest that severity of NASH and susceptibility to NASH may be determined by variations in miRNA expression response. More importantly, our data provide a mechanistic link between alterations in miRNA expression and pathophysiological and pathomorphological features of NASH.

Upregulated microRNA-199a-5p inhibits nuclear receptor corepressor 1 translation in mice with non-alcoholic steatohepatitis

“…2), indicating that the diet induced the characteristic steatosis pathology, mixed hepatic inflammatory and fibrosis, signifying a successful NASH model. (19) demonstrated that feeding C57BL/6J mice a methyl-deficient diet to induce NASH results in aberrant expression of miRNAs, including miR-122, miR-199a-5p and miR-221. To investigate the role of these three miRNAs in NASH, the levels of miR-122, miR-199a-5p and miR-221 were determined in the livers extracted from mice fed MCD and control diets, using RT-PCR experiments.…”

“…Alterations in the expression levels of miR-29c, miR-34a, miR-155 and miR-200b, hepatic miRNAs, were associated with differences in the pathophysiological and pathomorphological features of NASH (19). Furthermore, in a study screening for altered expression levels of hepatic miRNAs associated with NASH, a total of 23 miRNAs were reported to be underexpressed or overexpressed in NASH, with the predicted targets of these miRNAs known to affect cell proliferation, metabolism, protein translation, apoptosis, inflammation and oxidative stress (20).…”

Epigenetic mechanisms elicited by nutrition in early life

“…, Sun et al (23) Diallyl disulfide (garlic) Histone modifications Cancer prevention Ficz et al (15) , Delage & Dashwood (16) High-cholesterol diet MicroRNAs Obesity Pogribny et al (26) High-fat diet DNA methylation Obesity; metabolic syndrome Buckley et al (45) , Khan et al (46,47) Dietary methyl deficiency MicroRNAs Non-alcoholic steatohepatitis; liver cancer…”

MicroRNAs in Liver Disease: Bench to Bedside

“…14,36 Notably, miR-34a has been shown to be up-regulated in both human serum 50,51 and liver in humans and animal models of NAFLD. 14,55,121,122 Two recent studies suggest two differing mechanisms for the involvement of miR-34a in NASH pathogenesis through down-regulation of SIRT-1; a) leading to AMP kinase dephosphorylation and subsequent decreased phosphorylation of HMGCoA, ultimately leading to cholesterol accumulation 121 ; b) increased acetylation of p53 causing activation of apoptosis. 123 MiR-122 is significantly down-regulated in humans and animal models of NAFLD patients.…”