Contribution of Cdc42 to cholesterol efflux in fibroblasts from Tangier disease and Werner syndrome.
Atherosclerotic cardiovascular disease is a life-threatening disorder. Cholesterol efflux from the cells is the rate-limiting step in regulating the intracellular cholesterol content as well as raft structure in the plasma membrane. The defect of cholesterol efflux leads to the development of atherosclerosis. Tangier disease (TD), a hereditary high-density lipoprotein deficiency, is characterized by the presence of defective cellular cholesterol efflux. Using the cDNA subtraction technique, we found that expression of Cdc42 was decreased markedly in fibroblasts and macrophages from patients with TD. Madin-Darby canine kidney cells expressing the dominant-negative form of Cdc42 had a reduced lipid efflux; inversely, cells expressing the active form had increased efflux. Furthermore, we found that cellular lipid efflux was defective and Cdc42 was reduced in fibroblasts from a premature aging disorder, Werner syndrome. Complementation experiments using an adenovirus carrying wild-type Cdc42 successfully corrected impaired lipid efflux in Werner syndrome cells. We concluded that Cdc42 may play important roles in cellular cholesterol efflux and that dysregulation of this type of RhoGTPase might lead to the development of atherosclerotic cardiovascular disease.
Hirano
Ken-ichi
K
Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
Ikegami
Chiaki
C
Zhang
Zhongyan
Z
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000378:metabolism*; D004285:Dogs; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D008264:Macrophages / Q000502:physiology; D013631:Tangier Disease / Q000503:physiopathology*; D014898:Werner Syndrome / Q000503:physiopathology*; D020764:cdc42 GTP-Binding Protein / Q000502:physiology*
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D002784:Cholesterol; D020764:cdc42 GTP-Binding Protein