Fat-specific Protein 27 Regulates Storage of Triacylglycerol

Abstract

FSP27 (fat-specific protein 27) is a member of the cell deathinducing DNA fragmentation factor-␣-like effector (CIDE) family. Although Cidea and Cideb were initially characterized as activators of apoptosis, recent studies have demonstrated important metabolic roles for these proteins. In this study, we investigated the function of another member of this family, FSP27 (Cidec), in apoptosis and adipocyte metabolism. Although overexpression of FSP27 is sufficient to increase apoptosis of 293T and 3T3-L1 cells, more physiological levels of expression stimulate spontaneous lipid accumulation in several cell types without induction of adipocyte genes. Increased triacylglycerol is likely due to decreased ␤-oxidation of nonesterified fatty acids. Altered flux of fatty acids into triacylglycerol may be a direct effect of FSP27 function, which is localized to lipid droplets in 293T cells and 3T3-L1 adipocytes. Stable knockdown of FSP27 during adipogenesis of 3T3-L1 cells substantially decreases lipid droplet size, increases mitochondrial and lipid droplet number, and modestly increases glucose uptake and lipolysis. Expression of FSP27 in subcutaneous adipose tissue of a human diabetes cohort decreases with total fat mass but is not associated with measures of insulin resistance (e.g. homeostasis model assessment). Together, these data indicate that FSP27 binds to lipid droplets and regulates their enlargement.The cell death-inducing DNA fragmentation factor-␣-like effector (CIDE) 5 family of proteins shares sequence similarity with DNA fragmentation factors and was initially characterized as mitochondrial activators of apoptosis (1, 2). However, strong metabolic phenotypes of mice lacking Cidea and Cideb indicate that this family plays critical roles in energy balance (3, 4). Cidea knock-out mice are lean and resistant to diet-induced obesity because of increased lipolysis and mitochondrial uncoupling in brown adipose tissue (3). Although expression of Cidea is limited to brown adipocytes in mice, humans express CIDE-A in white adipose tissue, where lower levels are observed with obesity and insulin resistance (5, 6). Although a coding variant of CIDE-A, V115F, is associated with human obesity (7), knockdown of CIDE-A in human adipocytes enhances lipolysis (5).Cideb knock-out mice are also lean and resistant to diet-induced obesity; however, this family member is expressed highly in liver, and the phenotype is because of decreased hepatic lipogenesis, increased fatty acid oxidation, and increased whole body energy expenditure (4). Thus, through a number of mechanisms, the CIDE family appears to have important roles in lipid metabolism. FSP27 (fat-specific protein of 27 kDa or Cidec) is the third member of the CIDE family. FSP27 was identified prior to the other family members based upon induction during adipogenesis (8). CIDE-3, the human version of FSP27, was characterized as 66% homologous to mouse and as an activator of apoptosis when expressed in 293T cells (9). However, the lack of function ascribed to FSP27 limit...

Dietary supplementation with soy isoflavones or replacement with soy proteins prevents hepatic lipid droplet accumulation and alters expression of genes involved in lipid metabolism in rats

“…FSP27, originally identified as a cell-death-inducing DFF45-like effector C, was shown to be lipid-droplet-associated protein and promote the formation of lipid droplet by enhancing TG accumulation within lipid droplets and regulating fat storage (Puri et al 2007(Puri et al , 2008Keller et al 2008). Overexpression of FSP27 in the liver of the leptin-deficient (ob/ob) mouse increased hepatic TG content (Matsusue et al 2008).…”

Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis

“…In liver, loss of ROR␣ affected the expression of many genes that regulate lipid homeostasis. The cell death-inducing DFFA-like effector c (Cidec), also termed fat-specific protein (FSP27), and cell death-inducing DFFA-like effector a (Cidea), two proteins that play a critical role in triglyceride accumulation (26,39,62), and monoacylglycerol O-acyltransferase 1 (Mogat1), which is part of an alternative pathway of triglyceride synthesis, were among the genes most strongly suppressed in ROR␣ sg/sg liver. The expression of several other genes implicated in fatty acid homeostasis was also repressed in ROR␣ sg/sg liver.…”

Functional analysis of FSP27 protein regions for lipid droplet localization, caspase-dependent apoptosis, and dimerization with CIDEA

“…Moreover, in addition to being lipid droplet-localized proteins per se, ectopic expression of FSP27 and CIDEA has been demonstrated to promote the formation and/or enlargement of lipid droplets in several nonadipocyte cell types, a phenomenon that is particularly evident with addition of exogenous oleic acid to culture media. This has been shown for FLAG-tagged FSP27 in 3T3-L1 preadipocytes (12) and for eGFP-FSP27 in 3T3-L1 preadipocytes, 293T, and COS cells (12,25). For CIDEA, FLAG-tagged CIDEA has been demonstrated to promote lipid droplet formation in 3T3-L1 preadipocytes (12).…”

“…However, recent studies strongly suggest that this localization was incorrect and that FSP27, CIDEA, and CIDEB are lipid droplet-associated proteins (12,21,25,33,42). Signal for an FSP27-enhanced green fluorescent protein (eGFP) fusion protein has been shown to be colocalized to lipid droplets in 3T3-L1 adipocytes and lipid-loaded 293T cells (12).…”