Role of hepatic protein arginine methyltransferase 1 in obesity-induced metabolic disorders

Abstract

Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent liver disease characterized by high intrahepatic triglyceride accumulation due to various causes other than excessive alcohol consumption. NAFLD is strongly associated with obesity and type 2 diabetes (T2D). However, it is observed that a certain number of obese subjects will not develop NAFLD or T2D, suggesting the complex mechanisms underlying the lipid and glucose metabolism of NAFLD.

Protein arginine methyltransferase (PRMT) 1 is a predominant type I protein arginine methyltransferase that accounts for more than 85% of all cellular PRMT activities. It has been intensively studied in histone arginine methylations and their roles in chromatin dynamics as well as transcriptional regulation. However, the role of PRMT1 in metabolic diseases is poorly understood. As the elevated expression levels of hepatic PRMT1 was observed in dietary obesity induced NAFLD mice, it is of worth to explore the function of PRMT1 in NAFLD. Therefore, this study aims to investigate: (1) whether PRMT1 plays a pathophysiological role in the regulation of dietary obesity induced NAFLD; (2) the mechanism underlying the role of PRMT1 in dietary obesity induced NAFLD.

In this study, a novel role of PRMT1 in protection against dietary obesity induced NAFLD was first identified. Liver-specific overexpression of PRMT1 in mice markedly ameliorated hepatic steatosis as well as liver injury upon long-term high-fat diet (HFD) feeding which was associated with significantly improved glucose tolerance and insulin sensitivity when compared to HFD-fed control mice. Hepatic fatty acid oxidation (FAO) rate was observed significantly elevated in mice with overexpression of PRMT1 which explains why overexpression of PRMT1 can alleviate NAFLD in HFD-fed mice. Furthermore, our data demonstrated that the methyltransferase activity of PRMT1 is required for its protective role against NAFLD.

Mechanistically, PRMT1 induces hepatic FAO rates via its substrate peroxisome proliferator-activated receptor gamma coactivator 1-𝛼 (PGC-1𝛼), a key regulator in controlling hepatic FAO process. It was shown that the protective effects of PRMT1 against NAFLD was significantly abolished by knock-down of endogenous PGC-1𝛼. However, it was not achieved by direct PGC-1𝛼 methylation. Instead, dramatic increase in PGC-1𝛼 mRNA and protein expression levels was observed in the liver of mice with PRMT1 overexpression. Furthermore, putative binding sites of hepatocyte nuclear factor-4𝛼 (HNF-4𝛼), a transcription factor regulated by PRMT1, was predicted in the promoter region of PGC-1𝛼. By using luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay, the binding of HNF-4𝛼 on the chromatin of PGC-1𝛼 was identified in the presence of enzymatic active PRMT1. More importantly, hepatic expression level of PRMT1 was found to be inversely correlated with the development of simple steatosis and positively correlated with the expression levels PGC-1𝛼 in obese human subjects that is consistent with the animal findings.

Collectively, these data indicate that the role of hepatic PRMT1 in protection against dietary obesity induced NAFLD is facilitated by the transcriptional activation of PGC-1𝛼 via the methyltransferase activity of PRMT1.