Abstract
The mechanism controlling long-chain fatty acid (LCFA) mobilization from adipose tissue is not well understood. Here, we investigated how the LCFA transporter CD36 regulates this process. By using tissue-specific KO mouse models, we showed that CD36 in adipocytes and endothelial cells mediated both LCFA deposition into and release from adipose tissue. We demonstrated the role of adipocytic and endothelial CD36 in promoting tumor growth and chemoresistance conferred by adipose tissue–derived LCFAs. We showed that dynamic cysteine S-acylation of CD36 in adipocytes, endothelial cells, and cancer cells mediated intercellular LCFA transport. We demonstrated that lipolysis induction in adipocytes triggered CD36 deacylation and deglycosylation, as well as its dissociation from interacting proteins, prohibitin-1 (PHB) and annexin 2 (ANX2). Our data indicate that lipolysis triggers caveolar endocytosis and translocation of CD36 from the cell membrane to lipid droplets. This study suggests a mechanism for both outside-in and inside-out cellular LCFA transport regulated by CD36 S-acylation and its interactions with PHB and ANX2.
Highlights
Overgrowth and dysfunction of white adipose tissue (WAT) in obesity is associated with type 2 diabetes and other life-threatening diseases, including cancer [1,2,3,4,5]
To determine whether the adipose tissue phenotype is due to abnormal long-chain fatty acid (LCFA) uptake, we i.v. injected mice with a fluorophore-labeled palmitic acid, BODIPY-FL-C16, and analyzed adipocytes recovered from adipose tissue after 180 minutes of circulation
BODIPY-FL-C16 accumulation was markedly lower in adipocytes from visceral, subcutaneous, and brown adipose tissue in CD36 Ad-KO and endothelial cells (ECs)-KO mice compared with WT controls (Figure 1C)
Summary
Overgrowth and dysfunction of white adipose tissue (WAT) in obesity is associated with type 2 diabetes and other life-threatening diseases, including cancer [1,2,3,4,5]. Type 2 diabetes and other metabolic diseases, as well as some cancers, are aggravated by excessive mobilization of lipids from adipocytes. Adipocyte lipolysis is observed during advanced stages of many carcinomas [8], and recent evidence indicates a key role of adipocyte-derived fatty acids hijacked by cancer cells [9, 10]. Long-chain fatty acids (LCFAs) confer cancer cells with metastatic properties and chemoresistance [11]. Adipocytes adjacent to tumors clearly serve as a source of LCFAs for cancer cells [12,13,14]. Contribution of LCFAs mobilized into the circulation from WAT not directly in contact with tumors may contribute at advanced cancer stages when lipolysis becomes systemic
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