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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2707.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Hepatic PGC-1β Overexpression Induces Combined Hyperlipidemia and Modulates the Response to PPAR Activation

Christopher J. Lelliott; Anna Ljungberg; Andrea Ahnmark; Lena William-Olsson; Kim Ekroos; Anders Elmgren; Gunnel Arnerup; Carol C. Shoulders; Jan Oscarsson; Daniel Lindén

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.

Correspondence to Daniel Lindén, AstraZeneca R&D, Department of Integrative Pharmacology (HE119), SE-431 83 Mölndal, Sweden. 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)-1β, and that in vitro both PGC-1β 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-1β. On chow, hepatic PGC-1β 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-1β overexpression blunted Wy-mediated changes in expression levels of PPAR and downstream genes. Furthermore, PGC-1β did not potentiate Wy-stimulated fatty acid oxidation in primary hepatocytes. PGC-1β and PGC-1 overexpression did not alter SREBP-1c, SREBP-1c target gene expression, nor hepatic triglyceride content. On HFD, PGC-1β overexpression decreased hepatic SREBP-1c, yet increased FAS and ACC mRNA and plasma triglyceride levels.

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

The effects of increased hepatic expression of PGC-1 or PGC-1β on PPAR activation, gene expression, and lipid metabolism were investigated. PGC-1β overexpression induced a combined hyperlipidemia and blunted the effects of PPAR activation on gene expression. Thus, inhibition of hepatic PGC-1β may ameliorate combined hyperlipidemia and improve the effects of PPAR activators.

Key Words: DGAT • apolipoprotein B • adenovirus • hepatic lipase • hypertriglyceridemia

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