Hepatic PRMT1 ameliorates diet-induced hepatic steatosis via induction of PGC1α

Abstract

Rationale : Over-nutrition will lead to overexpression of PRMT1 but protein hypomethylation is observed in the liver of obese subjects. The dynamic alteration of the expression and methyltransferase activity of PRMT1 in the progression of fatty liver diseases remains elusive. Methods : We used recombinant adeno-associated virus-mediated gene delivery system to manipulate the hepatic PRMT1 expression level in diet-induced obese mice to investigate the role of PRMT1 in hepatic steatosis. We further utilized a cohort of obese humans with biopsy-proven nonalcoholic fatty liver disease to support our observations in mouse model. Results : We demonstrated that knockdown of PRMT1 promoted steatosis development in liver of high-fat diet (HFD) fed mice. Over-expression of wild-type PRMT1, but not methyltransferase-defective mutant PRMT1 G80R , could alleviate diet-induced hepatic steatosis. The observation is conserved in the specimens of obese humans with biopsy-proven nonalcoholic fatty liver disease. Mechanistically, methyltransferase activity of PRMT1 was required to induce PGC-1α mRNA expression via recruitment of HNF-4α to the promoter of PGC-1α, and hence attenuated HFD-induced hepatic steatosis by enhancing PGC-1α-mediated fatty acid oxidation. Conclusions : Our results identify that activation of the PRMT1/HNF-4α/PGC-1α signaling is a potential therapeutic strategy for combating non-alcoholic fatty liver disease of obese subjects.

From metabolism to malignancy: the multifaceted role of PGC1α in cancer

“…Liver cirrhosis, stemming from non-alcoholic fatty liver disease (NAFLD), occasionally precedes HCC and involves Bcl-3 ( 78 ), while Bcl-3 reduces PGC1α activity, suggesting that higher PGC1α activity might protect against NAFLD-related liver cirrhosis ( 78 , 79 ). Indeed, pharmacologically activating PGC1α has shown promise for NAFLD treatment ( 78 , 80 ).…”

Amelioration of non-alcoholic fatty liver disease by targeting G protein-coupled receptor 110: A preclinical study

“…Primary hepatocytes from different groups of mice were isolated using a two-step perfusion method as previously described [28,29]. Briefly, type II collagenase was perfused to mice at a flow rate of 10 ml/min.…”

“…Representative histopathological images were acquired with a light microscope (Olympus, Tokyo, Japan). Western blot analysis was performed as previously described [25,26,28,29]. Briefly, total protein was extracted from tissues and cultured cells with RIPA lysis buffer (65 mM Tris-HCl pH 7.5, 150 mM NaCl, 1 mM EDTA, 1% NP-40, 0.5% sodium deoxycholate and 0.1% SDS).…”

“…Primary antibodies used were shown in Table S1. Liver biopsy specimens were collected from 9 biopsy-proven NAFLD patients [33]. Liver sections with H&E staining were subjected to histological evaluation of steatosis.…”

Non-coding RNAs: The link between maternal malnutrition and offspring metabolism

“…Overexpression of miR-29a in C2C12 (skeletal muscle cell line) decreased the levels of glucose transporter 4 (GLUT4) and also downregulated its target gene peroxisome proliferator-activated receptor δ (PPARδ), thereby reducing PGC1α expression ( Figure 1 ) ( 122 ). In contrast, overexpression of PGC1α can mediate fatty acid oxidation, attenuating HFD-induced hepatic steatosis ( 124 ). Interestingly, in clinical studies, Ortiz-Dosal et al ( 102 ) quantified miRNAs associated with metabolic diseases in dried blood spots of newborns with adequate birth weight, low birth weight (LBW) or macrosomia.…”