title: Adipose tissue deficiency results in severe hyperlipidemia and atherosclerosis in the low-density lipoprotein receptor knockout mice.
abstract: Adipose tissue can store over 50% of whole-body cholesterol; however, the physiological role of adipose tissue in cholesterol metabolism and atherogenesis has not been directly assessed. Here, we examined lipoprotein metabolism and atherogenesis in a unique mouse model of severe lipodystrophy: the Seipin(-/-) mice, and also in mice deficient in both low-density lipoprotein receptor (Ldlr) and Seipin: the Ldlr(-/-)Seipin(-/-) mice. Plasma cholesterol was moderately increased in the Seipin(-/-) mice when fed an atherogenic diet. Strikingly, plasma cholesterol reached ~6000 mg/dl in the Seipin(-/-)Ldlr(-/-) mice on an atherogenic diet, as compared to ~1000 mg/dl in the Ldlr(-/-) mice on the same diet. The Seipin(-/-)Ldlr(-/-) mice also developed spontaneous atherosclerosis on chow diet and severe atherosclerosis on an atherogenic diet. Rosiglitazone treatment significantly reduced the hypercholesterolemia of the Seipin(-/-)Ldlr(-/-) mice, and also alleviated the severity of atherosclerosis. Our results provide direct evidence, for the first time, that the adipose tissue plays a critical role in the clearance of plasma cholesterol. Our results also reveal a previously unappreciated strong link between adipose tissue and LDLR in plasma cholesterol metabolism.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Mengyu
authors.initials: M
authors.lastname: Wang
authors.affiliation: Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Gao
authors.affiliation: Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Liao
authors.affiliation: School of Biotechnology and Biomolecular Sciences, the University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Qi
authors.affiliation: School of Biotechnology and Biomolecular Sciences, the University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Ximing
authors.initials: X
authors.lastname: Du
authors.affiliation: Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing 100191, China. Electronic address: georgeliu@bjmu.edu.cn.
authors.forename: George
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; School of Biotechnology and Biomolecular Sciences, the University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: h.rob.yang@unsw.edu.au.
authors.forename: Hongyuan
authors.initials: H
authors.lastname: Yang
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D050154:Adiposity; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D044388:GTP-Binding Protein gamma Subunits; D020022:Genetic Predisposition to Disease; D020962:Heterotrimeric GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D000077154:Rosiglitazone; D012720:Severity of Illness Index; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors
chemical_list: C115783:Bscl2 protein, mouse; D044388:GTP-Binding Protein gamma Subunits; D000960:Hypolipidemic Agents; D011973:Receptors, LDL; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D002784:Cholesterol; D020962:Heterotrimeric GTP-Binding Proteins
keywords: Adipose tissue; Cholesterol; Hypercholesterolemia; Lipodystrophy; Seipin