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)

Research output: Contribution to journalArticleScientificpeer-review

34 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

Fingerprint

PPAR alpha
Peroxisome Proliferator-Activated Receptors
Hyperlipidemias
Liver
Sterol Regulatory Element Binding Protein 1
Gene Expression
High Fat Diet
Triglycerides
Messenger RNA
Apolipoproteins B
Lipase
Inbred C57BL Mouse
Lipid Metabolism
Adenoviridae
Hepatocytes
Fatty Acids
Lipids

Keywords

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

Cite this

Lelliott, Christopher J. ; Ljungberg, Anna ; Ahnmark, Andrea ; William-Olsson, Lena ; Ekroos, Kim ; Elmgren, Anders ; Arnerup, Gunnel ; Shoulders, Carol C. ; Oscarsson, Jan ; Lindén, Daniel. / Hepatic PGC-1{beta} overexpression induces combined hyperlipidemia and modulates the response to PPAR{alpha} activation. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2007 ; Vol. 27, No. 12. pp. 2707-2713.
@article{b86d001b14094b5396560134c38c8d72,
title = "Hepatic PGC-1{beta} overexpression induces combined hyperlipidemia and modulates the response to PPAR{alpha} activation",
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.",
keywords = "DGAT, apolipoprotein B, adenovirus, hepatic lipase, hypertriglyceridemia",
author = "Lelliott, {Christopher J.} and Anna Ljungberg and Andrea Ahnmark and Lena William-Olsson and Kim Ekroos and Anders Elmgren and Gunnel Arnerup and Shoulders, {Carol C.} and Jan Oscarsson and Daniel Lind{\'e}n",
year = "2007",
doi = "10.1161/ATVBAHA.107.155739",
language = "English",
volume = "27",
pages = "2707--2713",
journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
issn = "1079-5642",
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}

Lelliott, CJ, Ljungberg, A, Ahnmark, A, William-Olsson, L, Ekroos, K, Elmgren, A, Arnerup, G, Shoulders, CC, 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, vol. 27, no. 12, pp. 2707-2713. https://doi.org/10.1161/ATVBAHA.107.155739

Hepatic PGC-1{beta} overexpression induces combined hyperlipidemia and modulates the response to PPAR{alpha} activation. / Lelliott, Christopher J.; Ljungberg, Anna; Ahnmark, Andrea; William-Olsson, Lena; Ekroos, Kim; Elmgren, Anders; Arnerup, Gunnel; Shoulders, Carol C.; Oscarsson, Jan; Lindén, Daniel (Corresponding Author).

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 27, No. 12, 2007, p. 2707-2713.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Hepatic PGC-1{beta} overexpression induces combined hyperlipidemia and modulates the response to PPAR{alpha} activation

AU - Lelliott, Christopher J.

AU - Ljungberg, Anna

AU - Ahnmark, Andrea

AU - William-Olsson, Lena

AU - Ekroos, Kim

AU - Elmgren, Anders

AU - Arnerup, Gunnel

AU - Shoulders, Carol C.

AU - Oscarsson, Jan

AU - Lindén, Daniel

PY - 2007

Y1 - 2007

N2 - 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.

AB - 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.

KW - DGAT

KW - apolipoprotein B

KW - adenovirus

KW - hepatic lipase

KW - hypertriglyceridemia

U2 - 10.1161/ATVBAHA.107.155739

DO - 10.1161/ATVBAHA.107.155739

M3 - Article

VL - 27

SP - 2707

EP - 2713

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

SN - 1079-5642

IS - 12

ER -