Published online Dec 14, 2017. doi: 10.3748/wjg.v23.i46.8140
Peer-review started: August 25, 2017
First decision: October 11, 2017
Revised: October 16, 2017
Accepted: October 27, 2017
Article in press: October 27, 2017
Published online: December 14, 2017
Based on the “multiple hit” theory of non-alcoholic fatty liver disease (NAFLD) pathogenesis, lipid accumulation initiates simple hepatic steatosis and subsequently triggers multiple insults, ultimately inducing non-alcoholic steatohepatitis, cirrhosis, and even hepatocellular carcinoma. In addition to the classical factors involved in the progression of NAFLD, microRNAs, which represent epigenetic alterations, have been identified as important post-transcriptional regulators in the pathogenesis of this disease.
Due to the abundance of miR-192-5p in the liver, many researchers have focused on miR-192-5p as a serum biomarker of liver injury, such as drug-induced liver injury, chronic hepatitis B, hepatocellular carcinoma, and NAFLD. Because microRNAs are important regulators in a wide spectrum of biological processes and metabolic homeostasis, the role of microRNAs in NAFLD pathogenesis is of particular interest. Our previous research in NAFLD patients found that serum miR-192-5p levels could differentiate different stages of NAFLD and showed good correlations with hepatic steatosis and inflammatory activity, but little is known about its regulatory role in lipid metabolism.
We aimed to evaluate the hepatic levels of miR-192-5p in rat models of NAFLD, and figure out the role of miR-192-5p in lipid metabolism. After the present study, we have identified the lipogenetic gene SCD-1 as a target gene of miR-192-5p, confirming the negative regulatory effect of miR-192-5p in lipid synthesis in NAFLD. These realized objectives give us a better understanding about the functional mechanism of miR-192-5p in NALFD and provide a new insight in the miRNA-intervention treatment strategy for this disease.
We conducted this study in HFD-fed rats and palmitic acid-treated Huh7 cells. The hepatic and hepatocellular levels of miR-192-5p in NAFLD were evaluated using quantitative real-time polymerase chain reaction both in vivo and in vitro. The SCD-1 protein levels were examined by Western blot analysis. Oil red O staining and TG assay were used to detect the lipid accumulation in rat livers and hepatocytes. Overexpression and knockdown of miR-192-5p were performed in Huh7 cells with miR-192-5p mimic and inhibitor. Luciferase reporter assays confirmed the direct interaction between miR-192-5p and SCD-1.
In the current study, we found that miR-192-5p decreased in NAFLD both in vivo and in vitro and the decrease could be reversed after disease remission by liraglutide therapy in animal models. Meanwhile, we confirmed that miR-192-5p had a negative regulatory role in lipid synthesis, which was mediated through its regulation on lipogenetic gene SCD-1. However, the specific regulatory role of miR-192-5p in NAFLD patients remains unclear, which needs to be validated in clinical studies.
The authors demonstrated that miR-192-5p decreased in NAFLD conditions both in vivo and in vitro, which could provide more evidence for the clinical use of circulating miR-192-5p as a biomarker in NAFLD. We first confirmed that miR-192-5p showed direct regulation on lipogenetic gene SCD-1 and that this could mediate the negative regulatory effect of miR-192-5p in lipid synthesis in NAFLD. These data complement the regulators involved in the progression of NAFLD and help us better understand the role of epigenetic factors in this disease. Meanwhile, the study suggests that the overexpression of miR-192-5p may reflect a promising treatment strategy for NAFLD, which calls for more validated data in the future.
This study suggests that the miRNA intervention may be a promising treatment strategy for NAFLD. The future study might focus on the specific regulatory role of miR-192-5p in NAFLD in vivo, and the therapeutic effect of miR-192-5p needs to be validated in clinical practice. It would be of practical implications if clinical experiments support our claims going forward.