Hyperglycemia suppresses hepatic scavenger receptor class B type I expression.
Hyperglycemia is a major risk factor for atherosclerotic disease. Hepatic scavenger receptor class B type I (SR-BI) binds HDL particles that mediate reverse cholesterol transport and thus lowers the risk of atherosclerosis. Here we examined glucose regulation of SR-BI gene expression in both HepG2 cells and whole animals. Results showed that hepatic SR-BI mRNA, protein, and uptake of cholesterol from HDL were halved following 48 h of exposure to 22.4 vs. 5.6 mM glucose. As in the case of the cell culture model, hepatic expression of SR-BI was lower in diabetic rats than in euglycemic rats. Transcriptional activity of the human SR-BI promoter paralleled endogenous expression of the gene, and this activity was dependent upon the dose of glucose. Next, we used inhibitors of select signal transduction pathways to demonstrate that glucose suppression of SR-BI was sensitive to the p38 MAPK inhibitor. Expression of a constitutively active p38 MAPK inhibited SR-BI promoter activity in the presence or absence of glucose. A dominant-negative p38 MAPK abolished the inhibitory effect of glucose on promoter activity. Deletional analysis located a 50-bp fragment of the promoter that mediated the effects of glucose. Within this DNA fragment there were several specificity protein-1 (Sp1) binding sites, and cellular knockdown of Sp1 abrogated its suppression by glucose. Together, these results indicate that the glucose suppression of SR-B1 expression is partially mediated by the activation of the p38 MAPK-Sp1 pathway and raise the possibility that the inhibition of hepatic SR-BI expression under high-glucose conditions provides a mechanism for accelerated atherosclerosis in diabetics.
Murao
Koji
K
Div. of Endocrinology and Metabolism, Dept. of Internal Medicine, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan. mkoji@kms.ac.jp
Yu
Xiao
X
Imachi
Hitomi
H
Cao
Wen M
WM
Chen
Ke
K
Matsumoto
Kensuke
K
Nishiuchi
Takamasa
T
Wong
Norman C W
NC
Ishida
Toshihiko
T
D050197:Atherosclerosis / Q000503:physiopathology*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D003925:Diabetic Angiopathies / Q000503:physiopathology*; D015870:Gene Expression / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology*; D008113:Liver Neoplasms; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000502:physiology; D051122:Scavenger Receptors, Class B / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D016329:Sp1 Transcription Factor; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose