title: The therapeutic role of very low-density lipoprotein receptor gene in hyperlipidemia in type 2 diabetic rats.
abstract: Hyperlipidemia is a common feature of type 2 diabetes and is related to cardiovascular disease. The very low-density lipoprotein receptor (VLDLR) binds to and internalizes triglyceride-rich lipoproteins with high specificity. In this study, we evaluated the role of VLDLR in hyperlipidemia in type 2 diabetic rats. Type 2 diabetes was induced in male Wistar rats by injection of low-dose streptozotocin coupled with a high-fat diet. Recombinant adeno-associated viral (rAAV) vectors encoding the human VLDLR gene (rAAV·VLDLR) were intravenously administered to diabetic rats. Results showed that in vivo, total VLDLR mRNA and protein levels were significantly decreased in skeletal muscle (type I VLDLR mainly reduced) and adipose tissue (type II VLDLR mainly reduced) but not in heart in hypercholesterolemic, hypertriglyceridemic diabetic rats compared with normal rats. And in vitro, in 3T3-L1 adipocytes, insulin-induced (1.0 mmol/liter) insulin resistance significantly decreased VLDLR mRNA expression. In rats, rAAV·VLDLR delivery resulted in a reduction in serum cholesterol and triglyceride that lasted for the duration of the study (12 weeks). Fasting blood insulin was significantly lower in the rAAV·VLDLR group versus untreated diabetic rats although fasting blood glucose levels were not significantly different in both groups at the end of the study. rAAV·VLDLR-treated animals had significantly increased lipoprotein lipase activity and reduced aortic atherosclerosis. Taken together, our data suggest that type 2 diabetes and related insulin resistance manifest decreased VLDLR with elevated serum cholesterol and triglyceride levels, and overexpression of VLDLR through a single injection of rAAV·VLDLR reversed these effects and consequentially attenuated aorta atherosclerotic plaque progression.
authors.affiliation: Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors.forename: Gang
authors.initials: G
authors.lastname: Yuan
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Liu
authors.forename: Tingting
authors.initials: T
authors.lastname: Sun
authors.forename: Yongping
authors.initials: Y
authors.lastname: Xu
authors.forename: Jianhuan
authors.initials: J
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Muxun
authors.initials: M
authors.lastname: Zhang
authors.forename: Katherine
authors.initials: K
authors.lastname: Cianflone
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000473:pathology; D001786:Blood Glucose; D001835:Body Weight / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D000229:Dependovirus / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D006949:Hyperlipidemias / Q000473:pathology / Q000628:therapy*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D011973:Receptors, LDL; D014280:Triglycerides; C036053:VLDL receptor; D002784:Cholesterol