Hepatic ACAT2 Knock Down Increases ABCA1 and Modifies HDL Metabolism in Mice

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

doi:10.1371/journal.pone.0093552

Abstract

ObjectivesACAT2 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.DesignWT 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.ResultsASO6 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.ConclusionsThe 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.

Highlights

For many years, the inhibition of intracellular cholesterol esterification has been considered as a potential strategy to prevent atherosclerosis [1]
ACAT2 seems to be a hepatic player affecting the cholesterol fluxes fated to VLDL or to HDL, the latter via up-regulation of ABCA1
In agreement with previous studies [13], ASO6 administration led to a specific down-regulation of ACAT2 in the liver (Figure 1 A) without modifying the expression in proximal or distal intestine (Figure 1 B, C)

Summary

Introduction

The inhibition of intracellular cholesterol esterification has been considered as a potential strategy to prevent atherosclerosis [1]. Athero-protection was achieved in mice using anti-sense oligonucleotide targeted to hepatic Soat mRNA (ASO6) and resulting in a decreased ACAT2 activity in the liver [10]. These studies did not address whether a decreased hepatic ACAT2 activity modifies HDL metabolism. In DOKO mice the link between ACAT2 activity and HDL metabolism should be more evident This mouse model is characterized by a reduced bile acid (BA) synthesis, which is paralleled by a maintained ABCA1 expression in the liver. We investigated whether the metabolic response following a decreased hepatic ACAT2 activity was influenced by the time frame in which the animals were fed a western type of diet

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Conclusion