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Role of Acyl‐Coenzyme A:Cholesterol Acyltransferase 1 in Lipogenesis in Adipocytes
Author(s) -
Zhu Yuyan,
Chen ChihYu,
Kim KeeHong
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.248.7
Subject(s) - lipogenesis , adipogenesis , sterol o acyltransferase , sterol regulatory element binding protein , endocrinology , medicine , gene knockdown , sterol , chemistry , lipid droplet , cholesterol , biology , lipid metabolism , biochemistry , adipose tissue , lipoprotein , gene
Dysregulated lipogenesis in adipose tissue contributes to obesity and its metabolic disorders. However, the molecular mechanisms regulating lipogenesis in adipocytes are not fully understood. Acyl‐coenzyme A: cholesterol acyltransferase (ACAT), an enzyme that catalyzes the formation of cholesteryl ester from free cholesterol (FC), has been identified as a therapeutic target to treat atherosclerosis. However, the role of ACAT in adipogenesis and lipogenesis in adipocytes is unknown. Here, we employed both pharmaceutical inhibitors and a lentivirus‐mediated shRNA‐based gene knockdown technique to investigate the role of ACAT in adipogenesis using murine 3T3‐L1 preadipocytes as an in vitro model of adipogenesis. Avasimibe, an ACAT inhibitor, was added at non‐toxic concentrations and replaced every other day during the course of adipogenesis. Avasimibe treatment inhibited lipid accumulation in a dose‐dependent manner, as judged by Oil red O staining and thin layer chromatography. Consistently, ACAT1 knockdown in 3T3‐L1 cells reduced lipid droplet accumulation by 40%. Real‐time PCR revealed that ACAT inhibition down‐regulated expressions of sterol regulatory element‐binding protein‐1 and genes involved in lipogenesis, with little effect on adipogenic transcription factors. These results suggest that ACAT is required for lipid droplet biogenesis in adipocytes. In addition, ACAT inhibition reduced 37% of intracellular FC and impaired cholesterol uptake in adipocytes, indicating a role of ACAT1 in the biochemical link between lipogenesis and cholesterol homeostasis. Taken together, our results reveal a novel function of ACAT1 in lipogenesis and highlight an important role of ACAT1 in integrating cholesterol metabolism and neutral lipid synthesis in adipocytes.