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

Zhihao Jia; Feng Yue; Xiyue Chen; Naagarajan Narayanan; Jiamin Qiu; Sabriya A Syed; Anthony N Imbalzano; Meng Deng; Peng Yu; Changdeng Hu; Shihuan Kuang

doi:10.1002/advs.202002602

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

Adv Sci (Weinh). 2020 Oct 16;7(23):2002602. doi: 10.1002/advs.202002602. eCollection 2020 Dec.

Authors

Zhihao Jia¹, Feng Yue¹, Xiyue Chen¹, Naagarajan Narayanan^{2

3}, Jiamin Qiu¹, Sabriya A Syed⁴, Anthony N Imbalzano⁴, Meng Deng^{2

3}, Peng Yu^{5

6}, Changdeng Hu^{7

8}, Shihuan Kuang^{1

8}

Affiliations

¹ Department of Animal Sciences Purdue University West Lafayette IN 47907 USA.
² Department of Agricultural and Biological Engineering Purdue University West Lafayette IN 47907 USA.
³ Bindley Bioscience Center Purdue University West Lafayette IN 47907 USA.
⁴ Department of Biochemistry and Molecular Pharmacology University of Massachusetts Medical School Worcester MA 01605 USA.
⁵ West China Biomedical Big Data Center West China Hospital Sichuan University Chengdu 610041 China.
⁶ Medical Big Data Center Sichuan University Chengdu 610041 China.
⁷ Department of Medicinal Chemistry and Molecular Pharmacology Purdue University West Lafayette Indiana 47907 USA.
⁸ Purdue University Center for Cancer Research West Lafayette Indiana 47907 USA.

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.

Keywords: BSCL2; adipocytes; lipodystrophy; methylation; type 2 diabetes.

Abstract

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