Open AccessHepatic ACAT2 Knock Down Increases ABCA1 and Modifies HDL Metabolism in Mice
Author(s) -
Matteo Pedrelli,
Padideh Davoodpour,
Chiara Degirolamo,
Monica Gomaraschi,
Mark Graham,
Alice Ossoli,
Lars-Olof Larsson,
Laura Calabresi,
JanÅke Gustafsson,
Knut R. Steffensen,
Mats Eriksson,
Paolo Parini
Publication year - 2014
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0093552
Subject(s) - abca1 , endocrinology , medicine , cholesteryl ester , cholesterol , metabolism , apolipoprotein e , lipid metabolism , very low density lipoprotein , knockout mouse , chemistry , apolipoprotein b , high density lipoprotein , lipoprotein , biology , biochemistry , disease , gene , receptor , transporter
Objectives ACAT2 is the exclusive cholesterol-esterifying enzyme in hepatocytes and enterocytes. Hepatic ABCA1 transfers unesterified cholesterol (UC) to apoAI, thus generating HDL. By changing the hepatic UC pool available for ABCA1, ACAT2 may affect HDL metabolism. The aim of this study was to reveal whether hepatic ACAT2 influences HDL metabolism. Design WT and LXRα/β double knockout (DOKO) mice were fed a western-type diet for 8 weeks. Animals were i.p. injected with an antisense oligonucleotide targeted to hepatic ACAT2 (ASO6), or with an ASO control. Injections started 4 weeks after, or concomitantly with, the beginning of the diet. Results ASO6 reduced liver cholesteryl esters, while not inducing UC accumulation. ASO6 increased hepatic ABCA1 protein independently of the diet conditions. ASO6 affected HDL lipids (increased UC) only in DOKO, while it increased apoE-containing HDL in both genotypes. In WT mice ASO6 led to the appearance of large HDL enriched in apoAI and apoE. Conclusions The use of ASO6 revealed a new pathway by which the liver may contribute to HDL metabolism in mice. ACAT2 seems to be a hepatic player affecting the cholesterol fluxes fated to VLDL or to HDL, the latter via up-regulation of ABCA1.