ACAT1/SOAT1 maintains adipogenic ability in preadipocytes by regulating cholesterol homeostasis

Qing Liu; Xiaolin Wu; Wei Duan; Xiaohan Pan; Martin Wabitsch; Ming Lu; Jing Li; Li-Hao Huang; Zhangsen Zhou; Yuyan Zhu

doi:10.1016/j.jlr.2024.100680

ACAT1/SOAT1 maintains adipogenic ability in preadipocytes by regulating cholesterol homeostasis

J Lipid Res. 2024 Oct 30;65(12):100680. doi: 10.1016/j.jlr.2024.100680. Online ahead of print.

Authors

Qing Liu¹, Xiaolin Wu¹, Wei Duan², Xiaohan Pan¹, Martin Wabitsch³, Ming Lu², Jing Li⁴, Li-Hao Huang⁵, Zhangsen Zhou², Yuyan Zhu⁶

Affiliations

¹ Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon, Hung Hom, Hong Kong; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hung Hom, Hong Kong.
² Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
³ Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany.
⁴ Department of Computing, The Hong Kong Polytechnic University, Kowloon, Hung Hom, Hong Kong.
⁵ Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Liver Cancer Institute Zhongshan Hospital, Fudan University, Shanghai, China.
⁶ Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon, Hung Hom, Hong Kong; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hung Hom, Hong Kong; Research Institute for Future Food, The Hong Kong Polytechnic University, Kowloon, Hung Hom, Hong Kong; The Hong Kong Polytechnic University Shenzhen Research Institute, The Hong Kong Polytechnic University, Shenzhen, China. Electronic address: yuyan.zhu@polyu.edu.hk.

PMID: 39481851
DOI: 10.1016/j.jlr.2024.100680

Abstract

Maintaining cholesterol homeostasis is critical for preserving adipocyte function during the progression of obesity. Despite this, the regulatory role of cholesterol esterification in governing adipocyte expandability has been understudied. Acyl-coenzyme A (CoA):cholesterol acyltransferase/Sterol O-acyltransferase 1 (ACAT1/SOAT1) is the dominant enzyme to synthesize cholesteryl ester in most tissues. Our previous study demonstrated that knockdown of either ACAT1 or ACAT2 impaired adipogenesis. However, the underlying mechanism of how ACAT1 mediates adipogenesis remains unclear. Here, we reported that ACAT1 is the dominant isoform in white adipose tissue of both humans and mice, and knocking out ACAT1 reduced fat mass in mice. Furthermore, ACAT1-deficiency inhibited the early stage of adipogenesis via attenuating PPARγ pathway. Mechanistically, ACAT1 deficiency inhibited SREBP2-mediated cholesterol uptake and thus reduced intracellular and plasma membrane cholesterol levels during adipogenesis. Replenishing cholesterol could rescue adipogenic master gene-Pparγ's-transcription in ACAT1-deficient cells during adipogenesis. Finally, overexpression of catalytically functional ACAT1, not the catalytic-dead ACAT1, rescued cholesterol levels and efficiently rescued the transcription of PPARγ as well as the adipogenesis in ACAT1-deficient preadipocytes. In summary, our study revealed the indispensable role of ACAT1 in adipogenesis via regulating intracellular cholesterol homeostasis.

Keywords: PPARγ; adipocytes; cholesterol/metabolism; cholesterol/trafficking; cholesteryl ester; lipid rafts; nuclear receptors/SREBP.