Protein Arginine Methyltransferase PRMT5 Regulates Fatty Acid Metabolism and Lipid Droplet Biogenesis in White Adipose Tissues

Abstract The protein arginine methyltransferase 5 (PRMT5) is an emerging regulator of cancer and stem cells including adipogenic progenitors. Here, a new physiological role of PRMT5 in adipocytes and systemic metabolism is reported. Conditional knockout mice were generated to ablate the Prmt5 gene specifically in adipocytes (Prmt5 AKO ). The Prmt5 AKO mice exhibit sex‐ and depot‐dependent progressive lipodystrophy that is more pronounced in females and in visceral (than subcutaneous) white fat. The lipodystrophy and associated energy imbalance, hyperlipidemia, hepatic steatosis, glucose intolerance, and insulin resistance are exacerbated by high‐fat‐diet. Mechanistically, Prmt5 methylates and releases the transcription elongation factor SPT5 from Berardinelli‐Seip congenital lipodystrophy 2 ( Bscl2 , encoding Seipin) promoter, and Prmt5 AKO disrupts Seipin‐mediated lipid droplet biogenesis. Prmt5 also methylates Sterol Regulatory Element‐Binding Transcription Factor 1a (SREBP1a) and promotes lipogenic gene expression, and Prmt5 AKO suppresses SREBP1a‐dependent fatty acid metabolic pathways in adipocytes. Thus, PRMT5 plays a critical role in regulating lipid metabolism and lipid droplet biogenesis in adipocytes.