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Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2707-13. Epub 2007 Oct 11.

Hepatic PGC-1beta overexpression induces combined hyperlipidemia and modulates the response to PPARalpha activation.

Author information

1
AstraZeneca R&D, Department of Integrative Pharmacology (HE119), SE-431 83 Mölndal, Sweden.

Abstract

OBJECTIVE:

Previous studies have indicated that the hyperlipidemia and gene expression changes induced by a short-term high-fat diet (HFD) are mediated through the peroxisome proliferator-activated receptor gamma coactivator (PGC)-1beta, and that in vitro both PGC-1beta and PGC -1alpha increase PPARalpha-mediated transcriptional activities. Here, we examined the in vivo effects of these two coactivators in potentiating the lipid lowering properties of the PPARalpha agonist Wy14,643 (Wy).

METHODS AND RESULTS:

C57BL/6 mice were fed chow or HFD and transduced with adenoviruses encoding PGC-1alpha or PGC-1beta. On chow, hepatic PGC-1beta overexpression caused severe combined hyperlipidemia including elevated plasma apolipoprotein B levels. Hepatic triglyceride secretion, DGAT1, and FAT/CD36 expression were increased whereas PPARalpha and hepatic lipase mRNA levels were reduced. PGC-1beta overexpression blunted Wy-mediated changes in expression levels of PPARalpha and downstream genes. Furthermore, PGC-1beta did not potentiate Wy-stimulated fatty acid oxidation in primary hepatocytes. PGC-1beta and PGC-1alpha overexpression did not alter SREBP-1c, SREBP-1c target gene expression, nor hepatic triglyceride content. On HFD, PGC-1beta overexpression decreased hepatic SREBP-1c, yet increased FAS and ACCalpha mRNA and plasma triglyceride levels.

CONCLUSIONS:

Hepatic PGC-1beta overexpression caused combined hyperlipidemia independent of SREBP-1c activation. Hepatic PGC-1beta overexpression reduced the potentially beneficial effects of PPARalpha activation on gene expression. Thus, inhibition of hepatic PGC-1beta may provide a therapy for treating combined hyperlipidemia.

PMID:
17932310
DOI:
10.1161/ATVBAHA.107.155739
[Indexed for MEDLINE]

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