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

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 (Prmt5AKO). The Prmt5AKO 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 Prmt5AKO disrupts Seipin‐mediated lipid droplet biogenesis. Prmt5 also methylates Sterol Regulatory Element‐Binding Transcription Factor 1a (SREBP1a) and promotes lipogenic gene expression, and Prmt5AKO 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. PRMT5 regulates protein function through methylating arginine residues. This study identifies two new functions of PRMT5 in adipocytes. First, PRMT5 methylates SPT5 to promote transcription of Bscl2 gene, whose mutation causes Bernardinelli‐Seip Congenital Lipodystrophy in humans. Second, PRMT5 methylates SREBP1a to regulate fatty acid metabolism. Mice lacking PRMT5 in adipocytes develop progressive lipodystrophy and insulin resistance, resembling BSCL2‐mutation disease.