PRMT3 Regulates Hepatic Lipogenesis Through Direct Interaction With LXRα

Abstract

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 α (LXRα). Thus we examined the pathophysiological role of PRMTs in NAFLD and their relationship with LXRα. 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 LXRα by directly binding with LXRα in a methylation-independent manner. In addition, PA treatment translocated PRMT3 to the nucleus. In animal models, a high-fat diet increased the LXRα and PRMT3 expressions and binding, which was not observed in LXRα KO mice. Furthermore, increased PRMT3 expression and its binding with LXRα were observed in NAFLD patients. Taken together, LXRα and PRMT3 expression was increased in cellular and mouse models of NAFLD and human patients, and PRMT3 translocated into the nucleus bound with LXRα as a transcriptional cofactor, which induced lipogenesis. In conclusion, PRMT3 translocation by PA is coupled to the binding of LXRα, which is responsible for the onset of fatty liver.

Inhibition of protein arginine methyltransferase 3 activity selectively impairs liver X receptor‐driven transcription of hepatic lipogenic genes in vivo

“…(2002). The mice received palm oil to further induce hepatic steatosis and ensure optimal stimulation of PRMT3 translocation to the nucleus (Chisholm et al ., 2003; Go et al ., 2015; Kim et al ., 2015a). To determine the effect of PRMT3 inhibition under these steatosis‐inducing conditions, mice were treated for 4 days with a total of three injections of SGC707 (30 mg·kg −1 ), which was the dose recommended for in vivo usage (Kaniskan et al ., 2015).…”

“…Kim et al . (2015a) suggested that PRMT3 functions as a selective LXR modulator in vitro . They have shown a specific induction of lipogenic genes via LXR in a PRMT3 overexpression model and reversal of these effects upon PRMT3 silencing and deletion.…”

“…Kim et al . (2015a,b) showed in vitro that PRMT3 and LXR co‐localize in the nucleus and that silencing of PRMT3 reduces both the expression of LXR and the binding of LXR to its target sequences. We show in our murine in vivo model that despite the obvious changes in hepatic lipogenesis, PRMT3 inhibition using SGC707 does not affect the cellular mRNA levels of LXR.…”

“…Based on this, 20(S)‐protopanaxatriol was shown to hamper the recruitment of TRAP80 to the target gene SREBP1c, thereby reducing the effect of this lipogenic co‐activator upon LXR stimulation (Oh et al ., 2015). Recently, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1254 (PRMT3) was identified as a novel co‐activator for LXR‐driven lipogenic gene expression in vitro (Kim et al, 2015a). In the current study, the in vivo relevance of PRMT3 as a specific co‐activator of LXR‐mediated hepatic lipogenesis is investigated, and the overall effect of PRMT3 inhibition on the therapeutic potential of LXR agonists is evaluated.…”

A Potent, Selective and Cell‐Active Allosteric Inhibitor of Protein Arginine Methyltransferase 3 (PRMT3)

“…[1] Recently it was shown that in cells treated with palmitic acid or T0901317 (a liver X receptor a (LXRa) agonist) PRMT3 co-localizes with LXRa in the cell nucleus, regulating hepatic lipogenesis. [2] However, this effect appears to be independent of PRMT3 methyltransferase activity. PRMT3 as well as PRMT1 meth-ylate the recombinant mammalian nuclear poly(A)-binding protein (PABPN1) [3] and have been implicated in oculophar-yngeal muscular dystrophy, which is caused by polyalanine expansion in PABPN1.…”