title: AAV8-mediated long-term expression of human LCAT significantly improves lipid profiles in hCETP;Ldlr(+/-) mice.
abstract: Lecithin:cholesterol acyltransferase (LCAT) is the key circulating enzyme responsible for high-density lipoprotein (HDL) cholesterol esterification, HDL maturation, and potentially reverse cholesterol transport. To further explore LCAT's mechanism of action on lipoprotein metabolism, we employed adeno-associated viral vector (AAV) serotype 8 to achieve long-term (32-week) high level expression of human LCAT in hCETP;Ldlr(+/-) mice, and characterized the lipid profiles in detail. The mice had a marked increase in HDL cholesterol, HDL particle size, and significant reduction in low-density lipoprotein (LDL) cholesterol, plasma triglycerides, and plasma apoB. Plasma LCAT activity significantly increased with humanized substrate specificity. HDL cholesteryl esters increased in a fashion that fits human LCAT specificity. HDL phosphatidylcholines trended toward decrease, with no change observed for HDL lysophosphatidylcholines. Triglycerides reduction appeared to reside in all lipoprotein particles (very low-density lipoprotein (VLDL), LDL, and HDL), with HDL triglycerides composition highly reflective of VLDL, suggesting that changes in HDL triglycerides were primarily driven by the altered triglycerides metabolism in VLDL. In summary, in this human-like model for lipoprotein metabolism, AAV8-mediated overexpression of human LCAT resulted in profound changes in plasma lipid profiles. Detailed lipid analyses in the lipoprotein particles suggest that LCAT's beneficial effect on lipid metabolism includes not only enhanced HDL cholesterol esterification but also improved metabolism of apoB-containing particles and triglycerides. Our findings thus shed new light on LCAT's mechanism of action and lend support to its therapeutic potential in treating dyslipidemia.
authors.affiliation: Atherosclerosis, Cardiovascular Diseases, Merck Research Laboratories, RY80T-A100, 126 E. Lincoln Ave, Rahway, NJ 07065, USA. zhu_chen@merck.com
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.forename: Donald
authors.initials: D
authors.lastname: Chu
authors.forename: Jose M
authors.initials: JM
authors.lastname: Castro-Perez
authors.forename: Weihua
authors.initials: W
authors.lastname: Ni
authors.forename: Aiwu
authors.initials: A
authors.lastname: Zhang
authors.forename: Mihajlo L
authors.initials: ML
authors.lastname: Krsmanovic
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.forename: Vinit
authors.initials: V
authors.lastname: Shah
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Stout
authors.forename: David G
authors.initials: DG
authors.lastname: McLaren
authors.forename: Alice C
authors.initials: AC
authors.lastname: Stefanni
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Roddy
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Plump
authors.forename: Brian K
authors.initials: BK
authors.lastname: Hubbard
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Vogt
authors.forename: Heather H
authors.initials: HH
authors.lastname: Zhou
mesh_terms: D000818:Animals; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008055:Lipids / Q000097:blood*; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010316:Particle Size; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics* / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008055:Lipids; D011973:Receptors, LDL; D007862:Phosphatidylcholine-Sterol O-Acyltransferase