Hepatic PGC-1{beta} overexpression induces combined hyperlipidemia and modulates the response to PPAR{alpha} activation

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

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37 Citations (Scopus)

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 γ coactivator (PGC)-1β, and that in vitro both PGC-1β and PGC −1α increase PPARα-mediated transcriptional activities. Here, we examined the in vivo effects of these two coactivators in potentiating the lipid lowering properties of the PPARα agonist Wy14,643 (Wy).

Methods and Results— C57BL/6 mice were fed chow or HFD and transduced with adenoviruses encoding PGC-1α 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 PPARα and hepatic lipase mRNA levels were reduced. PGC-1β overexpression blunted Wy-mediated changes in expression levels of PPARα and downstream genes.
Furthermore, PGC-1β did not potentiate Wy-stimulated fatty acid oxidation in primary hepatocytes. PGC-1β and PGC-1α 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 ACCα 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 PPARα 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-1α or PGC-1β on PPARα activation, gene expression, and lipid metabolism were investigated. PGC-1β overexpression induced a combined hyperlipidemia and blunted the effects of PPARα activation on gene expression.
Thus, inhibition of hepatic PGC-1β may ameliorate combined hyperlipidemia and improve the effects of PPARα activators.
Original languageEnglish
Pages (from-to)2707-2713
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume27
Issue number12
DOIs
Publication statusPublished - 2007
MoE publication typeA1 Journal article-refereed

Keywords

  • DGAT
  • apolipoprotein B
  • adenovirus
  • hepatic lipase
  • hypertriglyceridemia

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    Lelliott, C. J., Ljungberg, A., Ahnmark, A., William-Olsson, L., Ekroos, K., Elmgren, A., Arnerup, G., Shoulders, C. C., Oscarsson, J., & Lindén, D. (2007). Hepatic PGC-1{beta} overexpression induces combined hyperlipidemia and modulates the response to PPAR{alpha} activation. Arteriosclerosis, Thrombosis, and Vascular Biology, 27(12), 2707-2713. https://doi.org/10.1161/ATVBAHA.107.155739