Hepatic PGC-1beta overexpression induces combined hyperlipidemia and modulates the response to PPARalpha activation.
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 gamma coactivator (PGC)-1beta, and that in vitro both PGC-1beta and PGC -1alpha increase PPARalpha-mediated transcriptional activities. Here, we examined the in vivo effects of these two coactivators in potentiating the lipid lowering properties of the PPARalpha agonist Wy14,643 (Wy).


RESULTS
C57BL/6 mice were fed chow or HFD and transduced with adenoviruses encoding PGC-1alpha or PGC-1beta. On chow, hepatic PGC-1beta overexpression caused severe combined hyperlipidemia including elevated plasma apolipoprotein B levels. Hepatic triglyceride secretion, DGAT1, and FAT/CD36 expression were increased whereas PPARalpha and hepatic lipase mRNA levels were reduced. PGC-1beta overexpression blunted Wy-mediated changes in expression levels of PPARalpha and downstream genes. Furthermore, PGC-1beta did not potentiate Wy-stimulated fatty acid oxidation in primary hepatocytes. PGC-1beta and PGC-1alpha overexpression did not alter SREBP-1c, SREBP-1c target gene expression, nor hepatic triglyceride content. On HFD, PGC-1beta overexpression decreased hepatic SREBP-1c, yet increased FAS and ACCalpha mRNA and plasma triglyceride levels.


CONCLUSIONS
Hepatic PGC-1beta overexpression caused combined hyperlipidemia independent of SREBP-1c activation. Hepatic PGC-1beta overexpression reduced the potentially beneficial effects of PPARalpha activation on gene expression. Thus, inhibition of hepatic PGC-1beta may provide a therapy for treating combined hyperlipidemia.
Lelliott
Christopher J
CJ
AstraZeneca R&D, Department of Integrative Pharmacology (HE119), SE-431 83 Mölndal, Sweden.
Ljungberg
Anna
A
Ahnmark
Andrea
A
William-Olsson
Lena
L
Ekroos
Kim
K
Elmgren
Anders
A
Arnerup
Gunnel
G
Shoulders
Carol C
CC
Oscarsson
Jan
J
Lindén
Daniel
D
D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001055:Apolipoproteins B / Q000097:blood; D018955:CD36 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D051048:Diacylglycerol O-Acyltransferase / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D064429:Fatty Acid Synthases / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005822:Genetic Vectors; D006950:Hyperlipidemia, Familial Combined / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008049:Lipase / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D018110:Receptors, Lipoprotein / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014161:Transduction, Genetic; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation
D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D018955:CD36 Antigens; C008132:Cd36 protein, rat; D004041:Dietary Fats; D005227:Fatty Acids; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011743:Pyrimidines; D012333:RNA, Messenger; D018110:Receptors, Lipoprotein; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D015534:Trans-Activators; D014157:Transcription Factors; D014280:Triglycerides; C006253:pirinixic acid; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D064429:Fatty Acid Synthases; D008049:Lipase; C495700:Lipc protein, mouse; D000103:Acetyl-CoA Carboxylase