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Am J Physiol Endocrinol Metab (September 19, 2006). doi:10.1152/ajpendo.00157.2006
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Submitted on April 2, 2006
Accepted on September 17, 2006

PPAR-{alpha} Mediates the Hypolipidemic Action of Fibrates by Antagonizing FoxO1

Shen Qu1, Dongming Su1, Jennifer Altomonte2, Adama Kamagate3, Jing He1, German Perdomo1, Tonia Tse1, Yu Jiang4, and H. Henry Dong1*

1 Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
2 Department of Gene & Cell Medicine, Mount Sinai School of Medicine, New York, New York, United States
3 Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States
4 Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States

* To whom correspondence should be addressed. E-mail: dongh{at}pitt.edu.

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 FoxO1 production and promoted its nuclear redistribution in liver, correlating with augmented apoC-III production and impaired triglyceride metabolism. High fructose feeding upregulated PGC-1{beta} and SREBP-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 PPAR-{alpha}. PPAR-{alpha} 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. Counter-regulation of hepatic FoxO1 activity by PPAR-{alpha} constitutes an important mechanism by which fibrates act to curb apoC-III overproduction and ameliorate hypertriglyceridemia.




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