Fat-specific Protein 27 Inhibits Lipolysis by Facilitating the Inhibitory Effect of Transcription Factor Egr1 on Transcription of Adipose Triglyceride Lipase

Abstract

Background: FSP27 is a lipid droplet-associated protein.Results: Expression of FSP27 in human adipocytes reversely correlates with ATGL levels. Mechanistically, FSP27 increases the inhibitory effect of Egr1 on the ATGL promoter. Conclusion: FSP27 controls lipolysis by regulating ATGL transcription. Significance: Our study provides a new model of regulation of lipolysis in adipocytes. Current epidemics of metabolic diseases, such as type 2 diabetes, cardiac dysfunction, hypertension, hepatic steatosis, etc., are largely caused by widespread obesity. Although obesity can affect human health via several different mechanisms (1), the best established connection between obesity and metabolic disease is abnormal levels of circulating fatty acids (FA). 3 FA play important physiological roles in energy production and the synthesis of most lipids; nonetheless, their oversupply is highly detrimental as it leads to insulin resistance, oxidative stress, and other pathophysiological effects via mechanisms that are currently under intense investigation (1-5). Lipolysis in fat tissueNormally, dietary FA are partitioned into adipose tissue, converted into triglycerides, and stored in lipid droplets (LDs) that represent dynamic intracellular organelles consisting of a core of triglycerides and cholesterol esters, surrounded by a monolayer of phospholipids. Several proteins are associated with this monolayer, notably the PAT family proteins, PLIN 1-5 (6, 7), and fat-specific protein 27 (FSP27, also known as CIDEC) (8 -10). The latter protein plays an essential role in the regulation of LD morphology. Depletion of FSP27 in adipocytes leads to fragmentation of LDs (11,12), whereas overexpression of FSP27 increases the size of LDs while decreasing their number (8, 9, 12) by promoting LD fusion (13) and exchanging lipids from one droplet to another (14).It has also been demonstrated by us and others that FSP27 has anti-lipolytic activity (8,9,12,(15)(16)(17)(18). Lipolysis in adipose tissue is the major source of circulating . Correspondingly, unrestricted lipolysis in adipose tissue represents a serious metabolic defect and a causative factor of insulin resistance, diabetes mellitus, and other metabolic diseases (3,(25)(26)(27). As the mechanism of the anti-lipolytic activity of FSP27 is not completely clear, we decided to focus on this problem.Our recent study showed that FSP27 directly interacts with ATGL and regulates its lipase activity (18). Another study predicted that FSP27-mediated fusion of LDs might limit the access of intracellular lipases to the LD surface due to decreased surface area of larger LDs (17). As ATGL represents a major lipolytic enzyme (28), reducing its contact with LDs may suppress lipolysis.Here, we report another mechanism of the anti-lipolytic action of FSP27 in human adipocytes. We have found that FSP27 inhibits expression of ATGL at the level of transcription by stimulating the effect of its transcriptional repressor Egr1. EXPERIMENTAL PROCEDURESCell Culture-Human preadipocytes were procured from the ...

The life cycle of lipid droplets

“…First, Fsp27 binds directly to ATGL and inhibits lipolysis, both basal and hormone-stimulated, in an ATGL-dependent manner [50]. Second, Fsp27, a fraction of which resides in the nucleus, directly potentiates the negative regulation of Egr1 at the ATGL promoter [51]. ChIP analysis reveals both proteins bound to this promoter.…”

Negatively‐charged residues in the polar carboxy‐terminal region in FSP27 are indispensable for expanding lipid droplets

“…FSP27 was found to store TAG efficiently in cooperation with several proteins: perilipin 1 [17,22], adipose triacylglycerol lipase [23] and Egr1 [24]. In addition, FSP27 was reported to play a critical role in the development of hepatic steatosis [25][26][27][28][29].…”

Alcohol and Fat Promote Steatohepatitis: A Critical Role for Fat-Specific Protein 27/Cidec

“…17 There are several proteins, in addition to FSP27/CIDEC, which are involved in LD formation, notably the PAT ( p erilipin, a dipophilin, and the t ail-interacting protein of 47 kDa) family proteins, perilipin (PLIN 1–5). 141819 …”