RRC ID 67140
Author Takiguchi S, Ayaori M, Yakushiji E, Nishida T, Nakaya K, Sasaki M, Iizuka M, Uto-Kondo H, Terao Y, Yogo M, Komatsu T, Ogura M, Ikewaki K.
Title Hepatic Overexpression of Endothelial Lipase Lowers High-Density Lipoprotein but Maintains Reverse Cholesterol Transport in Mice: Role of Scavenger Receptor Class B Type I/ATP-Binding Cassette Transporter A1-Dependent Pathways.
Journal Arterioscler Thromb Vasc Biol
Abstract OBJECTIVE:Reverse cholesterol transport (RCT) is a major mechanism by which HDL (high-density lipoprotein) protects against atherosclerosis. Endothelial lipase (EL) reportedly reduces HDL levels, which, in theory, would increase atherosclerosis. However, it remains unclear whether EL affects RCT in vivo.
APPROACH AND RESULTS:Adenoviral vectors expressing EL or luciferase were intravenously injected into mice, and a macrophage RCT assay was performed. As expected, hepatic EL overexpression markedly reduced HDL levels. In parallel, plasma 3H-cholesterol counts from the EL-expressing mice decreased by 85% compared with control. Surprisingly, there was no difference in fecal 3H-cholesterol excretion between the groups. Kinetic studies revealed increased catabolism/hepatic uptake of 3HDL-cholesteryl ether, resulting in no change in fecal HDL-cholesteryl ester excretion in the mice. To explore underlying mechanisms for the preservation of RCT despite low HDL levels in the EL-expressing mice, we investigated the effects of hepatic SR-BI (scavenger receptor class B type I) knockdown. RCT assay revealed that knockdown of SR-BI alone reduced fecal excretion of macrophage-derived 3H-cholesterol. Interestingly, hepatic EL overexpression under SR-BI inhibition further attenuated fecal tracer counts as compared with control. Finally, we observed that EL overexpression enhanced in vivo RCT under pharmacological inhibition of hepatic ABCA1 (ATP-binding cassette transporter A1) by probucol.
CONCLUSIONS:Hepatic EL expression compensates for reduced macrophage-derived cholesterol efflux to plasma because of low HDL levels by promoting cholesterol excretion to bile/feces via an SR-BI pathway, maintaining overall RCT in vivo. In contrast, EL-modified HDL might negatively regulate RCT via hepatic ABCA1. Despite extreme hypoalphalipoproteinemia, RCT is maintained in EL-expressing mice via SR-BI/ABCA1-dependent pathways.
Volume 38(7)
Pages 1454-1467
Published 2018-7-1
DOI 10.1161/ATVBAHA.118.311056
PII ATVBAHA.118.311056
PMID 29748333
PMC PMC6039415
MeSH ATP Binding Cassette Transporter 1 / metabolism* Adenoviridae / genetics Animals Cholesterol, HDL / blood* Enzyme Induction Gene Transfer Techniques Genetic Vectors Hep G2 Cells Humans Lipase / biosynthesis* Lipase / genetics Liver / enzymology* Macrophages, Peritoneal / metabolism* Mice Mice, Inbred C57BL MicroRNAs / genetics MicroRNAs / metabolism RAW 264.7 Cells RNA Interference Scavenger Receptors, Class B / genetics Scavenger Receptors, Class B / metabolism*
IF 6.604
Resource
Human and Animal Cells Hep G2(RCB1886)