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

## TL;DR

PRMT5 regulates fat cell metabolism by controlling membrane transport and cholesterol synthesis, impacting energy balance and lipid composition.

## Contribution

This study reveals novel roles of PRMT5 in adipocyte metabolism through multiomics analyses.

## Key findings

- PRMT5 knockout alters gene expression related to glucose transport and fatty acid metabolism.
- PRMT5 regulates cholesterol biosynthesis, leading to hyperlipidemia and liver fat accumulation.
- Lipid composition changes include reduced triacylglycerols and increased glycerophospholipids.

## Abstract

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.

Prmt5

AKO
downregulates genes related to fatty acid (FA) uptake, triacylglycerol (TAG) biosynthesis, and FA oxidation, while upregulating genes involved in glucose transport and glycolysis.In addition, Prmt5

AKO
upregulates genes involved in peroxisomes and cholesterol biogenesis.These changes led to alterations in lipid composition, notably reduced TAG content and selective increases in glycerophospholipid and sphingolipid species.

Prmt5

AKO
downregulates genes related to fatty acid (FA) uptake, triacylglycerol (TAG) biosynthesis, and FA oxidation, while upregulating genes involved in glucose transport and glycolysis.

In addition, Prmt5

AKO
upregulates genes involved in peroxisomes and cholesterol biogenesis.

These changes led to alterations in lipid composition, notably reduced TAG content and selective increases in glycerophospholipid and sphingolipid species.

Prmt5

AKO
downregulates genes related to fatty acid transport and triacylglycerol synthesis, while upregulating genes involved in glucose transport and cholesterol biogenesis. These changes cause alternation in lipid composition and metabolic phenotypes of Prmt5

AKO
mice.