PPAR{alpha} mediates the hypolipidemic action of fibrates by antagonizing FoxO1.
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-gamma coactivator-1beta 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-alpha (PPARalpha). PPARalpha 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 PPARalpha constitutes an important mechanism by which fibrates act to curb apoC-III overproduction and ameliorate hypertriglyceridemia.
Qu
Shen
S
Rangos Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA 15213, USA.
Su
Dongming
D
Altomonte
Jennifer
J
Kamagate
Adama
A
He
Jing
J
Perdomo
German
G
Tse
Tonia
T
Jiang
Yu
Y
Dong
H Henry
HH
D000818:Animals; D053305:Apolipoprotein C-III / Q000378:metabolism; D001786:Blood Glucose / Q000032:analysis; D002478:Cells, Cultured; D006224:Cricetinae; D004032:Diet; D011345:Fenofibrate / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005632:Fructose / Q000008:administration & dosage; D005947:Glucose / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008055:Lipids / Q000032:analysis; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008297:Male; D047493:PPAR alpha / Q000502:physiology*
D053305:Apolipoprotein C-III; D001786:Blood Glucose; D051858:Forkhead Transcription Factors; D000960:Hypolipidemic Agents; D008055:Lipids; D047493:PPAR alpha; D005632:Fructose; D005947:Glucose; D011345:Fenofibrate