MiR-103-3p promotes hepatic steatosis to aggravate nonalcoholic fatty liver disease by targeting of ACOX1

Abstract

Background Nonalcoholic fatty liver disease (NAFLD) is a major risk factor for hepatocellular carcinoma, and alterations in miRNA expression are related to the development of NAFLD. However, the role of miRNAs in regulating the development of NAFLD is still poorly understood. Methods We used qRT-PCR to detect the level of miR-103-3p in both cell and mouse models of NAFLD. Biochemical assays, DCF-DA assays, Oil red O staining and HE staining were used to detect the role of miR-103-3p in NAFLD development. Target genes of miR-103-3p were predicted using the TargetScan database and verified by qRT-PCR, western blot and dual-luciferase assays. Results The expression of miR-103-3p increased in both NAFLD model cells and liver tissues from the NAFLD mouse model. Inhibition of miR-103-3p significantly alleviated the accumulation of lipid droplets in free fatty acid-treated L02 cells and liver tissues from mice with NAFLD. Inhibition of miR-103-3p reduced the contents of H2O2, TG, ALT, and AST and ROS production while increasing the ATP content. Moreover, the miR-103-3p antagomir alleviated liver tissue lesions in mice with NAFLD. Further studies identified ACOX1, a key enzyme for the oxidation and decomposition of fatty acids, as a direct target of miR-103-3p. Conclusions These findings identified a negative regulatory mechanism between ACOX1 and miR-103-3p that promotes the pathogenesis of NAFLD and suggested that inhibition of miR-103-3p may be a potential treatment strategy for NAFLD.

Therapeutic Effects of microRNAs on Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH): A Systematic Review and Meta-Analysis

“…It is, therefore, inferred that miRNA-103a-3p plays an essential role in NAFLD by its interaction through the HBP1 pathway. Furthermore, Ding et al [68] found increased expression of miRNA-103-3p both in FFA-treated L02 cells and in hepatocytes of NAFLD mice. The administration of miRNA-103-3p antagonists reduced lipid droplet aggregation in L02 cells and significantly reduced inflammatory responses, abnormal lipid metabolism, and oxidative stress in NAFLD mice.…”

Effect of diet and genotype on the miRNome of mice with altered lipoprotein metabolism

“… 41 Interestingly, a validated target gene for miR-103-3p is Acox1, the gene coding for acyl-CoA oxidase 1, the first and rate-limiting enzyme of the peroxisomal β-oxidation pathway. 42 Although there are no reports pointedly describing that a Pcsk9 deficiency leads to altered peroxisomal beta-oxidation, one article shows that a vaccination able to inhibit Pcsk9 activity resulted in increased Acox1 protein levels. 43 This may represent indirect evidence that, regardless of how it is obtained, the lack of Pcsk9 biological action determines a reduced expression of miR-103-3p that, in turns, promotes an increase in Acox1 protein levels.…”

miRNA biomarkers to predict risk of primary non-function of fatty allografts and drug induced acute liver failures

“…To evaluate different grades of hepatic steatosis on the regulation of blood borne miRNA, we compared plasma samples of patients diagnosed with mild to moderate steatosis (N = 7) to cases of marked steatosis (N = 7). Obviously, the number of patients is small, but even so, miRNA-103a-3p reached statistical signi cance and this miRNA promotes hepatic steatosis by repressing the expression of palmitoyl-CoA oxidase [37]. Furthermore, the expression of miRNA-26a-5p, miRNA-27b-3p, miRNA-103a-3p and miRNA-122-5p tended to be higher in cases of marked steatosis (supplementary Figure S6), however, did not reach statistical signi cance.…”