White adipose tissue (WAT) serves as a reversible energy storage depot in the form of lipids in response to nutritional status. Cavin-1, an essential component in the biogenesis of caveolae, is a positive regulator of lipolysis in adipocytes. However, molecular mechanisms of cavin-1 in the modulation of lipolysis remain poorly understood. Here, we showed that cavin-1 was acetylated at lysines 291, 293, and 298 (3K), which were under nutritional regulation in WAT. We further identified GCN5 as the acetyltransferase and Sirt1 as the deacetylase of cavin-1. Acetylationmimetic 3Q mutants of cavin-1 augmented fat mobilization in 3T3-L1 adipocytes and zebrafish. Mechanistically, acetylated cavin-1 preferentially interacted with hormone-sensitive lipase and recruited it to the caveolae, thereby promoting lipolysis. Our findings shed light on the essential role of cavin-1 in regulating lipolysis in an acetylation-dependent manner in WAT.KEYWORDS WAT, cavin-1, acetylation, HSL, lipolysis W hite adipose tissue (WAT) plays a critical role in regulating energy homeostasis, mostly by serving as a reversible energy storage depot in the body. Adipocytes store excess energy in the form of triglycerides (TAG), which can be hydrolyzed during nutrient shortage to release free fatty acids (FFA) and glycerol into circulation (1). Obesity is now epidemic and is accompanied by two dramatic effects on adipocyte function, a decrease in TAG synthesis and an increase in lipolysis (2). Abnormalities in the storage and utilization of TAG in WAT lead to high circulating plasma FFA levels, which promotes reesterification of lipids in other tissues (such as the liver) and exacerbates insulin resistance. This underscores the role of lipid metabolism in the pathogenesis of metabolic disorders, such as nonalcoholic fatty liver disease, type 2 diabetes, and atherosclerotic heart disease (3).Caveolae are small, omega-shaped invaginations of the plasma membrane of many cell types. Caveolae are especially abundant in adipocytes, and they play an important role in lipid trafficking and metabolism (4). Cavin-1, a conserved caveola coat protein required for caveola formation and function, also is involved in the regulation of lipid metabolism (5, 6). Human cavin-1 mutations have been reported in patients with congenital generalized lipodystrophy (7-13). Cavin-1 Ϫ/Ϫ mice have diminished adipose depot mass and smaller fat cells in WAT than wild-type (WT) mice, and in vitro cavin-1 null adipocytes display reduced lipolysis and fatty acid uptake and incorporation into lipids compared to WT adipocytes (14). Specific gain-and loss-of-function phenotypes of cavin-1 reveal its role as a positive regulator of lipolysis in 3T3-L1 adipocytes (15). However, molecular mechanisms by which cavin-1 promotes lipolysis in white adipocytes remain poorly understood. Several phosphorylation sites in the cavin-1 protein have been previously identified, and mutations of certain cavin-1 phosphorylation sites (S42A, T304A, or S368A) suppress lipolysis in 3T3-L1 adipocy...
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