Dong-il Kim,1 Min-jung Park,1 Seul-ki Lim,2 Jae-il Park,3 Kyung-chul Yoon,4 Ho-jae Han,5 Jan-Åke Gustafsson,6,7 Jae-hyang Lim,8 and Soo-hyun Park1 PRMT3 Regulates Hepatic Lipogenesis Through Direct Interaction With LXRa

Arginine methylation is responsible for diverse biological functions and is mediated by protein arginine methyltransferases (PRMTs). Nonalcoholic fatty liver disease (NAFLD) is accompanied by excessive hepatic lipogenesis via liver X receptor a (LXRa). Thus we examined the pathophysiological role of PRMTs in NAFLD and their relationship with LXRa. In this study, palmitic acid (PA) treatment increased PRMT3, which is correlated with the elevation of hepatic lipogenic proteins. The expression of lipogenic proteins was increased by PRMT3 overexpression, but decreased by PRMT3 silencing and use of the PRMT3 knockout (KO) mouse embryonic fibroblast cell line. PRMT3 also increased the transcriptional activity of LXRa by directly binding with LXRa in a methylation-independent manner. In addition, PA treatment translocated PRMT3 to the nucleus. In animal models, a high-fat diet increased the LXRa and PRMT3 expressions and binding, which was not observed in LXRa KO mice. Furthermore, increased PRMT3 expression and its binding with LXRa were observed in NAFLD patients. Taken together, LXRa and PRMT3 expression was increased in cellular and mouse models of NAFLD and human patients, and PRMT3 translocated into the nucleus bound with LXRa as a transcriptional cofactor, which induced lipogenesis. In conclusion, PRMT3 translocation by PA is coupled to the binding of LXRa, which is responsible for the onset of fatty liver. Nonalcoholic fatty liver disease (NAFLD) is a worldwide metabolic syndrome defined by an increased accumulation of fat, mainly triglycerides (TGs), within hepatocytes. NAFLD is closely related to diabetes because its pathogenesis is accompanied by hepatic insulin resistance and excessive hepatic lipogenesis (1,2). Many studies have been conducted to verify the molecular mechanism of lipogenesis. However, the whole mechanism is highly complex and difficult to understand. In the liver, liver X receptor a (LXRa) regulates SREBP1c and carbohydrate-responsive element-binding protein (ChREBP), which induce lipogenesis (3,4). LXRa that has been activated by oxysterol, an endogenous ligand, and/or T0901317, an exogenous ligand, increases the expression and transcriptional activity of SREBP1c and ChREBP and subsequently increases the transcription of fatty acid synthase (FAS) and acetyl CoA carboxylase (ACC), which are lipogenic enzymes (5–7). The transcriptional activity of LXRa is regulated by its interaction with its transcriptional cofactor, which determines whether binding with LXR response element (LXRE) will occur (8,9). LXRa-deficient mice have shown markedly lower hepatic expression of SREBP1c and its target genes (10). Moreover, T0901317induced hepatic expression of ACC and FAS was attenuated in ChREBP-knockout (KO) mice (4). Many studies have demonstrated the obvious role of LXRa in lipogenesis through SREBP1c and/or ChREBP, but recent studies