title: Dual regulation of adipose triglyceride lipase by pigment epithelium-derived factor: a novel mechanistic insight into progressive obesity.
abstract: Both elevated plasma free fatty acids (FFA) and accumulating triglyceride in adipose tissue are observed in the process of obesity and insulin resistance. This contradictory phenomenon and its underlying mechanisms have not been thoroughly elucidated. Recent studies have demonstrated that pigment epithelium-derived factor (PEDF) contributes to elevated plasma FFA and insulin resistance in obese mice via the activation of adipose triglyceride lipase (ATGL). However, we found that PEDF downregulated adipose ATGL protein expression despite of enhancing lipolysis. Plasma PEDF and FFA were increased in associated with a progressive high-fat-diet, and those outcomes were also accompanied by fat accumulation and a reduction in adipose ATGL. Exogenous PEDF injection downregulated adipose ATGL protein expression and elevated plasma FFA, while endogenous PEDF neutralization significantly rescued the adipose ATGL reduction and also reduced plasma FFA in obese mice. PEDF reduced ATGL protein expression in a time- and dose-dependent manner in differentiated 3T3-L1 cells. Small interfering RNA-mediated PEDF knockdown and antibody-mediated PEDF blockage increased endogenous ATGL expression, and PEDF overexpression downregulated ATGL. PEDF resulted in a decreased half-life of ATGL and regulated ATGL degradation via ubiquitin-dependent proteasomal degradation pathway. PEDF stimulated lipolysis via ATGL using ATGL inhibitor bromoenol lactone, and PEDF also downregulated G0/G1 switch gene 2 (G0S2) expression, which is an endogenous inhibitor of ATGL activation. Overall, PEDF attenuated ATGL protein accumulation via proteasome-mediated degradation in adipocytes, and PEDF also promoted lipolysis by activating ATGL. Elevated PEDF may contribute to progressive obesity and insulin resistance via its dual regulation of ATGL.
authors.affiliation: Department of Biochemistry, Zhongshan Medical School, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Dai
authors.forename: Weiwei
authors.initials: W
authors.lastname: Qi
authors.forename: Cen
authors.initials: C
authors.lastname: Li
authors.forename: Juling
authors.initials: J
authors.lastname: Lu
authors.forename: Yuling
authors.initials: Y
authors.lastname: Mao
authors.forename: Yachao
authors.initials: Y
authors.lastname: Yao
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Honghai
authors.initials: H
authors.lastname: Hong
authors.forename: Shuai
authors.initials: S
authors.lastname: Li
authors.forename: Ti
authors.initials: T
authors.lastname: Zhou
authors.forename: Zhonghan
authors.initials: Z
authors.lastname: Yang
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.forename: Guoquan
authors.initials: G
authors.lastname: Gao
authors.forename: Weibin
authors.initials: W
authors.lastname: Cai
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001835:Body Weight; D059305:Diet, High-Fat; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D004822:Epididymis / Q000378:metabolism / Q000473:pathology; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D008066:Lipolysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008954:Models, Biological; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009500:Neutralization Tests; D009765:Obesity / Q000201:enzymology* / Q000473:pathology; D009929:Organ Size; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D005230:Fatty Acids, Nonesterified; D008049:Lipase; D009414:Nerve Growth Factors; D046988:Proteasome Endopeptidase Complex; D015843:Serpins; D025801:Ubiquitin; D000099174:Pigment Epithelium-Derived Factor
keywords: ATGL; Free fatty acid; Lipolysis; Obesity; PEDF; Proteasome degradation pathway