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

C.J. Lelliott, A. Ljungberg, A. Ahnmark, L. William-Olsson, Kim Ekroos, A. Elmgren, G. Arnerup, C.C. Shoulders, J. Oscarsson, D. Linden (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

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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, C.J. ; Ljungberg, A. ; Ahnmark, A. ; William-Olsson, L. ; Ekroos, Kim ; Elmgren, A. ; Arnerup, G. ; Shoulders, C.C. ; Oscarsson, J. ; Linden, D. / 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.
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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 = "C.J. Lelliott and A. Ljungberg and A. Ahnmark and L. William-Olsson and Kim Ekroos and A. Elmgren and G. Arnerup and C.C. Shoulders and J. Oscarsson and D. Linden",
year = "2007",
doi = "10.1161/ATVBAHA.107.155739",
language = "English",
volume = "27",
pages = "2707--2713",
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Lelliott, CJ, Ljungberg, A, Ahnmark, A, William-Olsson, L, Ekroos, K, Elmgren, A, Arnerup, G, Shoulders, CC, Oscarsson, J & Linden, 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, C.J.; Ljungberg, A.; Ahnmark, A.; William-Olsson, L.; Ekroos, Kim; Elmgren, A.; Arnerup, G.; Shoulders, C.C.; Oscarsson, J.; Linden, D. (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, C.J.

AU - Ljungberg, A.

AU - Ahnmark, A.

AU - William-Olsson, L.

AU - Ekroos, Kim

AU - Elmgren, A.

AU - Arnerup, G.

AU - Shoulders, C.C.

AU - Oscarsson, J.

AU - Linden, D.

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 -