Activation of peroxisome proliferator-activated receptor-alpha in mice induces expression of the hepatic low-density lipoprotein receptor.
OBJECTIVE
Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolaemia in humans and deletion of the LDLR induces lesion development in mice fed a high-fat diet. LDLR expression is predominantly regulated by sterol regulatory element-binding protein 2 (SREBP2). Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARalpha) ligand, belongs to a drug class used to treat dyslipidaemic patients. We have investigated the effects of fenofibrate on hepatic LDLR expression.


METHODS
The effects of fenofibrate on hepatic LDLR expression (mRNA and protein) and function were evaluated by both in vitro (with AML12 cells) and in vivo experiments in mice.


RESULTS
Fenofibrate increased LDLR expression and LDL binding in a mouse hepatoma cell line, AML12 cells. Fenofibrate restored sterol-inhibited hepatocyte LDLR expression. Mechanistic studies demonstrated that induction of LDLR expression by fenofibrate was dependent on PPARalpha and sterol regulatory elements (SRE). Specifically, fenofibrate induced LDLR expression by increasing maturation of SREBP2 and phosphorylation of protein kinase B (Akt) but had no effect on SREBP cleavage-activating protein. In vivo, a high-fat diet suppressed LDLR expression in mouse liver while elevating total and LDL cholesterol levels in plasma. However, fenofibrate restored LDLR expression inhibited by high-fat diets in the liver and reduced LDL cholesterol levels in plasma.


CONCLUSIONS
Our data suggest that fenofibrate increased hepatic LDLR expression in mice by a mechanism involving Akt phosphorylation and LDLR gene transcription mediated by SREBP2.
Department of Pathology, Center of Vascular Biology, Weill Cornell Medical College, New York, NY 10065, USA.
Z
Z
Huang
X
X
Zhou
A C
AC
Nicholson
A M
AM
Gotto
D P
DP
Hajjar
J
J
Han
D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D011345:Fenofibrate / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D011973:Receptors, LDL / Q000187:drug effects* / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D008078:Cholesterol, LDL; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D011973:Receptors, LDL; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; D051057:Proto-Oncogene Proteins c-akt; D011345:Fenofibrate