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This Article Full Text Full Text (PDF) All Versions of this Article: 292/2/E421    most recent 00157.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Qu, S. Articles by Dong, H. H. Search for Related Content PubMed PubMed Citation Articles by Qu, S. Articles by Dong, H. H.

PPAR mediates the hypolipidemic action of fibrates by antagonizing FoxO1

¹Rangos Research Center, Children's Hospital of Pittsburgh, Department of Pediatrics, and ²Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and ³Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York

Submitted 2 April 2006 ; accepted in final form 17 September 2006

High-fructose consumption is associated with insulin resistance and diabetic dyslipidemia, but the underlying mechanism is unclear. We show in hamsters that high-fructose feeding stimulated forkhead box O1 (FoxO1) production and promoted its nuclear redistribution in liver, correlating with augmented apolipoprotein C-III (apoC-III) production and impaired triglyceride metabolism. High-fructose feeding upregulated peroxisome proliferator-activated receptor- coactivator-1 and sterol regulatory element binding protein-1c expression, accounting for increased fat infiltration in liver. High-fructose-fed hamsters developed hypertriglyceridemia, accompanied by hyperinsulinemia and glucose intolerance. These metabolic aberrations were reversible by fenofibrate, a commonly used anti-hypertriglyceridemia agent that is known to bind and activate peroxisome proliferator-activated receptor- (PPAR). PPAR physically interacted with, but functionally antagonized, FoxO1 in hepatic apoC-III expression. These data underscore the importance of FoxO1 deregulation in the pathogenesis of hypertriglyceridemia in high-fructose-fed hamsters. Counterregulation of hepatic FoxO1 activity by PPAR constitutes an important mechanism by which fibrates act to curb apoC-III overproduction and ameliorate hypertriglyceridemia.

hypertriglyceridemia; forkhead box O1; peroxisome proliferator-activated receptor-; apolipoprotein C-III; very-low-density lipoprotein-triglyceride; microsomal triglyceride transfer protein

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