MiR-155 Has a Protective Role in the Development of Non-Alcoholic Hepatosteatosis in Mice

Abstract

Hepatic steatosis is a global epidemic that is thought to contribute to the pathogenesis of type 2 diabetes. MicroRNAs (miRs) are regulators that can functionally integrate a range of metabolic and inflammatory pathways in liver. We aimed to investigate the functional role of miR-155 in hepatic steatosis. Male C57BL/6 wild-type (WT) and miR-155−/− mice were fed either normal chow or high fat diet (HFD) for 6 months then lipid levels, metabolic and inflammatory parameters were assessed in livers and serum of the mice. Mice lacking endogenous miR-155 that were fed HFD for 6 months developed increased hepatic steatosis compared to WT controls. This was associated with increased liver weight and serum VLDL/LDL cholesterol and alanine transaminase (ALT) levels, as well as increased hepatic expression of genes involved in glucose regulation (Pck1, Cebpa), fatty acid uptake (Cd36) and lipid metabolism (Fasn, Fabp4, Lpl, Abcd2, Pla2g7). Using miRNA target prediction algorithms and the microarray transcriptomic profile of miR-155−/− livers, we identified and validated that Nr1h3 (LXRα) as a direct miR-155 target gene that is potentially responsible for the liver phenotype of miR-155−/− mice. Together these data indicate that miR-155 plays a pivotal role regulating lipid metabolism in liver and that its deregulation may lead to hepatic steatosis in patients with diabetes.

Micro RNAs in the development of non-alcoholic fatty liver disease

“…These findings support a critical role for miR-122 in mediating the progression of steatosis to more clinically severe phenotypes and the subsequent development of cancer. An independent study also using knockout mice investigated the role of a second miRNA, miR-155, in the development of hepatic steatosis [26] . In that study, miR-155 -/-mice fed a high fat diet for six months developed significantly more hepatic steatosis, which was associated with increased liver weight and lipid levels, than C57BL/6 wildtype controls.…”

Regulation of MicroRNA 183 by Cyclooxygenase 2 in Liver Is DEAD-Box Helicase p68 (DDX5) Dependent: Role in Insulin Signaling

“…For example, Dávalos et al reported that miR33a/b contributes to the regulation of fatty acid and glucose metabolism and insulin signaling, by targeting key enzymes involved in fatty acid oxidation and IRS2 (45). Moreover, miR-155 has been shown to have a protective role in the development of nonalcoholic hepatosteatosis in mice, by regulating lipid metabolism through liver X receptor alpha (LXR␣) (46).…”

An Update on Microrna?s and Metabolic Regulation with Future Therapeutic Potentials Regarding Diagnosis and Treatment of Obesity, Metabolic Syndrome and Other Related Disorders

“…In line with these miR155 target genes, C/EBP beta (Cebpb) and Suppessor of cytokine signaling 3(Socs3) were decreased. miR155 is a multifunctional miRNA known to regulate numerous biological processes including haematopoiesis, inflammation, satherosclerosis and cancer [169]. Hence Miller et al reported that the absence of miR155 in mice fed HFD was associated with a significantly inceased hepatic steatosis andV LDL/LDL cholesterol levels and alanine transaminase (ALT) levels, as well as increased hepatic expression of genes involved in glucose regulation (Pck1,Cebpa), fatty acid uptake (CD36) and lipid metabolism (Fasn, Fabp4, Lpl, Abcd2Pla2g7).…”