FoxO6 integrates insulin signaling with MTP for regulating VLDL production in the liver.
Excessive production of triglyceride-rich very low-density lipoproteins (VLDL-TG) contributes to hypertriglyceridemia in obesity and type 2 diabetes. To understand the underlying mechanism, we studied hepatic regulation of VLDL-TG production by (forkhead box O6) FoxO6, a forkhead transcription factor that integrates insulin signaling to hepatic metabolism. We showed that transgenic mice expressing a constitutively active FoxO6 allele developed hypertriglyceridemia, culminating in elevated VLDL-TG levels and impaired postprandial TG clearance. This effect resulted in part from increased hepatic VLDL-TG production. We recapitulated these findings in cultured HepG2 cells and human primary hepatocytes, demonstrating that FoxO6 promoted hepatic VLDL-TG secretion. This action correlated with the ability of FoxO6 to stimulate hepatic production of microsomal triglyceride transfer protein (MTP), a molecular chaperone that catalyzes the rate-limiting step in VLDL-TG assembly and secretion. FoxO6 was shown to bind to the MTP promoter and stimulate MTP promoter activity in HepG2 cells. This effect was inhibited by insulin, consistent with the ability of insulin to promote FoxO6 phosphorylation and disable FoxO6 DNA-binding activity. Mutations of the FoxO6 target site within the MTP promoter abrogated FoxO6-mediated induction of MTP promoter activity. Hepatic FoxO6 expression became deregulated in insulin-resistant mice with obesity and type 2 diabetes. FoxO6 inhibition in insulin-resistant liver suppressed hepatic MTP expression and curbed VLDL-TG overproduction, contributing to the amelioration of hypertriglyceridemia in obese and diabetic db/db mice. These results characterize FoxO6 as an important signaling molecule upstream of MTP for regulating hepatic VLDL-TG production.
Division of Immunogenetics (D.H.K., T.Z., S.L., V.C.-N., J.Y., A.P., Y.F., H.H.D.) and Division of Genetics (R.U., E.G.), Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
Dae Hyun
DH
Kim
Ting
T
Zhang
Sojin
S
Lee
Virtu
V
Calabuig-Navarro
Jun
J
Yamauchi
Ann
A
Piccirillo
Yong
Y
Fan
Radha
R
Uppala
Eric
E
Goetzman
H Henry
HH
Dong
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D015228:Hypertriglyceridemia / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry; D008071:Lipoprotein Lipase / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014280:Triglycerides / Q000378:metabolism*
D002352:Carrier Proteins; D051858:Forkhead Transcription Factors; C525395:Foxo6 protein, mouse; D007328:Insulin; D008055:Lipids; D008079:Lipoproteins, VLDL; D047495:PPAR gamma; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; C030106:very low density lipoprotein triglyceride; D008071:Lipoprotein Lipase