Hepatic ACAT2 knock down increases ABCA1 and modifies HDL metabolism in mice

Matteo Pedrelli, Padideh Davoodpour, Chiara Degirolamo, Monica Gomaraschi, Mark Graham, Alice Ossoli, Lilian Larsson, Laura Calabresi, Jan Åke Gustafsson, Knut R. Steffensen, Mats Eriksson, Paolo Parini

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

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 LXRa/b 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.

Original languageEnglish (US)
Article numbere93552
JournalPLoS ONE
Volume9
Issue number4
DOIs
StatePublished - Apr 2 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Fingerprint Dive into the research topics of 'Hepatic ACAT2 knock down increases ABCA1 and modifies HDL metabolism in mice'. Together they form a unique fingerprint.

Cite this