Multiomics analyses reveal that PRMT5 regulates membrane transport and cholesterol synthesis in white adipocytes.

The adipose tissue (AT) is a main regulator of systemic energy homeostasis, and AT dysfunction leads to insulin resistance and other metabolic complications. Protein arginine methyltransferase 5 (PRMT5) catalyzes symmetrical dimethylation of arginine residues to modulate protein stability and function. Besides its well-studied oncogenic functions, PRMT5 has recently been shown to play a physiological role in AT through poorly understood mechanisms. Here, we explore the function of PRMT5 in AT through unbiased RNA sequencing and lipidomic analyses of AT in wild-type and adipocyte-specific Prmt5 knockout (Prmt5 AKO ) mice. Transcriptomic profiling revealed that Prmt5 AKO alters the expression of genes related to metabolism and membrane transport. Specifically, Prmt5 AKO induces genes enriched in glucose transport and glycolysis pathways, while suppressing genes encoding fatty acid (FA) transporters. Lipidomics analysis showed altered compositions of triacylglycerols (TAGs), fatty acids (FAs), and glycerophospholipids. Additionally, Prmt5 AKO promotes cholesterol biogenesis, associated with hyperlipidemia and hepatic steatosis in mice. These multiomics approaches uncover previously unappreciated roles of PRMT5 as an epigenetic regulator of metabolic homeostasis via coordinating membrane transport, balancing glucose and FA metabolism, and promoting cholesterol biosynthesis. This study highlights a novel mechanism by which protein methylation regulates systemic energy balance.