Hepatic PGC-1beta overexpression induces combined hyperlipidemia and modulates the response to PPARalpha activation.
Arterioscler Thromb Vasc Biol
; 27(12): 2707-13, 2007 Dec.
Article
em En
| MEDLINE
| ID: mdl-17932310
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 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). METHODS ANDRESULTS:
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.
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Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Transativadores
/
Regulação da Expressão Gênica
/
PPAR alfa
/
Hiperlipidemia Familiar Combinada
/
Fígado
/
Anticolesterolemiantes
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article