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


METHODS
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.
Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Molecular Nutrition Unit, Department of Bioscience and Nutrition, Karolinska Institutet, Stockholm, Sweden.
Matteo
M
Pedrelli
Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
Padideh
P
Davoodpour
Division of Lipid Science, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America.
Chiara
C
Degirolamo
Department of Pharmacological Sciences, University of Milan, Milan, Italy.
Monica
M
Gomaraschi
Cardiovascular Group, Department of Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, California, United States of America.
Mark
M
Graham
Department of Pharmacological Sciences, University of Milan, Milan, Italy.
Alice
A
Ossoli
Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
Lilian
L
Larsson
Department of Pharmacological Sciences, University of Milan, Milan, Italy.
Laura
L
Calabresi
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.
Jan-Åke
JÅ
Gustafsson
Molecular Nutrition Unit, Department of Bioscience and Nutrition, Karolinska Institutet, Stockholm, Sweden.
Knut R
KR
Steffensen
Molecular Nutrition Unit, Department of Bioscience and Nutrition, Karolinska Institutet, Stockholm, Sweden; Department of Medicine, Karolinska Institute, Stockholm, Sweden.
Mats
M
Eriksson
Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Molecular Nutrition Unit, Department of Bioscience and Nutrition, Karolinska Institutet, Stockholm, Sweden.
Paolo
P
Parini
D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D015536:Down-Regulation; D008075:Lipoproteins, HDL / Q000145:classification / Q000378:metabolism*; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016376:Oligonucleotides, Antisense; D002785:Sterol O-Acyltransferase / Q000235:genetics*; D000097587:Sterol O-Acyltransferase 2
D064286:ATP Binding Cassette Transporter 1; D008075:Lipoproteins, HDL; D016376:Oligonucleotides, Antisense; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2; C577833:Abca1 protein, mouse