title: Enhanced aortic atherosclerosis in transgenic Watanabe heritable hyperlipidemic rabbits expressing lipoprotein lipase.
abstract: OBJECTIVE
  This study was designed to address the effects of increased lipoprotein lipase (LPL) activity on atherosclerosis in the setting of LDL receptor deficiency.
  
  
  METHODS
  We generated transgenic (Tg) Watanabe heritable hyperlipidemic (WHHL) rabbits overexpressing human LPL and compared their plasma lipids and aortic atherosclerosis with non-Tg WHHL rabbits.
  
  
  RESULTS
  Increased expression of LPL significantly ameliorated hypertriglyceridemia and hypercholesterolemia in Tg WHHL rabbits [64% reduction in total cholesterol (TC) and 91% reduction in triglycerides (TG) vs. non-Tg]. In spite of this beneficial effect of LPL, Tg WHHL rabbits had two-fold greater aortic atherosclerosis than non-Tg WHHL rabbits. Analysis of plasma lipoprotein profiles revealed that increased LPL activity in Tg WHHL rabbits resulted in the dramatic reduction of large TG-rich lipoproteins (VLDL, d<1.006 g/ml and IDL, d=1.006-1.02) but concomitant increases in LDL fractions, especially those of small and dense LDL particles (d=1.04-1.06, 2.6-fold over non-Tg). Using apoB-containing lipoproteins, we found that small-sized LDL from Tg WHHL rabbits contained more oxidizable substrate and exhibited higher affinity to biglycan than large TG-rich LDL of non-Tg WHHL rabbits.
  
  
  CONCLUSIONS
  We conclude that in the absence of LDL receptor function, increased LPL activity accelerates the catabolism of large TG-rich VLDL (possibly via the LRP pathway) and subsequently improves hyperlipidemia. However, LPL may also enhance the generation and accumulation of small dense LDLs, which are more atherogenic.
authors.affiliation: Cardiovascular Disease Laboratory, Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Tomonari
authors.initials: T
authors.lastname: Koike
authors.forename: Jingyan
authors.initials: J
authors.lastname: Liang
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Wang
authors.forename: Tomonaga
authors.initials: T
authors.lastname: Ichikawa
authors.forename: Masashi
authors.initials: M
authors.lastname: Shiomi
authors.forename: Huijun
authors.initials: H
authors.lastname: Sun
authors.forename: Teruo
authors.initials: T
authors.lastname: Watanabe
authors.forename: George
authors.initials: G
authors.lastname: Liu
authors.forename: Jianglin
authors.initials: J
authors.lastname: Fan
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001011:Aorta / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D001055:Apolipoproteins B / Q000032:analysis; D001161:Arteriosclerosis / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D005260:Female; D006801:Humans; D006949:Hyperlipidemias / Q000201:enzymology* / Q000473:pathology; D007091:Image Processing, Computer-Assisted; D008071:Lipoprotein Lipase / Q000097:blood / Q000235:genetics*; D008074:Lipoproteins / Q000378:metabolism; D008297:Male; D008854:Microscopy, Electron; D011817:Rabbits; D014280:Triglycerides / Q000097:blood
chemical_list: D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D008074:Lipoproteins; D014280:Triglycerides; D002784:Cholesterol; D008071:Lipoprotein Lipase