on October 11, 2007
Published online before print October 11, 2007, doi: 10.1161/ATVBAHA.107.155739
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Submitted on September 10, 2007
Accepted on September 21, 2007
Hepatic PGC-1
Overexpression Induces Combined Hyperlipidemia and Modulates the Response to PPAR
Activation
Christopher J. Lelliott ;
From AstraZeneca R&D (C.J.L., A.L., A.A., L.W.-O., K.E., A.E., J.O., D.L.), Mölndal, Sweden; the Wallenberg Laboratory for Cardiovascular Research (A.L., K.E., J.O., D.L.) and the Department of Physiology/Endocrinology (A.L., J.O.), The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden; VTT Technical Research Centre of Finland (K.E.), Espoo, Finland; Safety Assessment Sweden, AstraZeneca R&D (G.A.), Södertälje, Sweden; and MRC Clinical Sciences Centre (C.C.S.), Imperial Collage London, London, UK.
* To whom correspondence should be addressed. E-mail: daniel.linden{at}astrazeneca.com.
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 
coactivator (PGC)-1
, and that in vitro both PGC-1 and PGC -1
increase PPAR-mediated transcriptional activities. Here, we examined the in vivo effects of these two coactivators in potentiating the lipid lowering properties of the PPAR agonist Wy14,643 (Wy).
Methods and Results—C57BL/6 mice were fed chow or HFD and transduced with adenoviruses encoding PGC-1 or PGC-1. On chow, hepatic PGC-1 overexpression caused severe combined hyperlipidemia including elevated plasma apolipoprotein B levels. Hepatic triglyceride secretion, DGAT1, and FAT/CD36 expression were increased whereas PPAR and hepatic lipase mRNA levels were reduced. PGC-1 overexpression blunted Wy-mediated changes in expression levels of PPAR and downstream genes. Furthermore, PGC-1 did not potentiate Wy-stimulated fatty acid oxidation in primary hepatocytes. PGC-1 and PGC-1 overexpression did not alter SREBP-1c, SREBP-1c target gene expression, nor hepatic triglyceride content. On HFD, PGC-1 overexpression decreased hepatic SREBP-1c, yet increased FAS and ACC mRNA and plasma triglyceride levels.
Conclusions—Hepatic PGC-1 overexpression caused combined hyperlipidemia independent of SREBP-1c activation. Hepatic PGC-1 overexpression reduced the potentially beneficial effects of PPAR activation on gene expression. Thus, inhibition of hepatic PGC-1 may provide a therapy for treating combined hyperlipidemia.
Key words: DGAT • apolipoprotein B • adenovirus • hepatic lipase • hypertriglyceridemia
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