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PLoS One. 2014 Apr 2;9(4):e93552. doi: 10.1371/journal.pone.0093552. eCollection 2014.

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

Author information

1
Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Molecular Nutrition Unit, Department of Bioscience and Nutrition, Karolinska Institutet, Stockholm, Sweden.
2
Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
3
Division of Lipid Science, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America.
4
Department of Pharmacological Sciences, University of Milan, Milan, Italy.
5
Cardiovascular Group, Department of Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, California, United States of America.
6
Molecular Nutrition Unit, Department of Bioscience and Nutrition, Karolinska Institutet, Stockholm, Sweden; Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas, United States of America.
7
Molecular Nutrition Unit, Department of Bioscience and Nutrition, Karolinska Institutet, Stockholm, Sweden.
8
Molecular Nutrition Unit, Department of Bioscience and Nutrition, Karolinska Institutet, Stockholm, Sweden; Department of Medicine, Karolinska Institute, Stockholm, Sweden.

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 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.

PMID:
24695360
PMCID:
PMC3973598
DOI:
10.1371/journal.pone.0093552
[Indexed for MEDLINE]
Free PMC Article
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