Liu Qing, Wu Xiaolin, Duan Wei, Pan Xiaohan, Wabitsch Martin, Lu Ming, Li Jing, Huang Li-Hao, Zhou Zhangsen, Zhu Yuyan
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.
Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
J Lipid Res. 2024 Dec;65(12):100680. doi: 10.1016/j.jlr.2024.100680. Epub 2024 Oct 30.
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.
在肥胖进展过程中维持胆固醇稳态对于保持脂肪细胞功能至关重要。尽管如此，胆固醇酯化在控制脂肪细胞扩张能力方面的调节作用尚未得到充分研究。酰基辅酶A（CoA）：胆固醇酰基转移酶/甾醇O-酰基转移酶1（ACAT1/SOAT1）是大多数组织中合成胆固醇酯的主要酶。我们之前的研究表明，敲低ACAT1或ACAT2会损害脂肪生成。然而，ACAT1介导脂肪生成的潜在机制仍不清楚。在此，我们报告ACAT1是人类和小鼠白色脂肪组织中的主要亚型，敲除ACAT1可降低小鼠的脂肪量。此外，ACAT1缺陷通过减弱PPARγ途径抑制脂肪生成的早期阶段。机制上，ACAT1缺陷抑制SREBP2介导的胆固醇摄取，从而降低脂肪生成过程中的细胞内和细胞膜胆固醇水平。补充胆固醇可以挽救ACAT1缺陷细胞在脂肪生成过程中脂肪生成主控基因Pparγ的转录。最后，催化功能正常的ACAT1而非催化失活的ACAT1的过表达挽救了胆固醇水平，并有效挽救了ACAT1缺陷前脂肪细胞中PPARγ的转录以及脂肪生成。总之，我们的研究揭示了ACAT1通过调节细胞内胆固醇稳态在脂肪生成中不可或缺的作用。
