FoxO6 Integrates Insulin Signaling With MTP for Regulating VLDL Production in the Liver

摘要: 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 VLDL-TG by (forkhead box O6) FoxO6, a forkhead transcription factor that integrates insulin signaling metabolism. We showed transgenic mice expressing constitutively active FoxO6 allele developed hypertriglyceridemia, culminating elevated levels impaired postprandial TG clearance. This effect resulted part from increased production. recapitulated these findings cultured HepG2 cells human primary hepatocytes, demonstrating promoted secretion. action correlated with ability stimulate microsomal triglyceride transfer protein (MTP), molecular chaperone catalyzes rate-limiting step assembly was shown bind MTP promoter activity cells. inhibited insulin, consistent promote phosphorylation disable DNA-binding activity. Mutations target site within abrogated FoxO6-mediated induction Hepatic expression became deregulated insulin-resistant inhibition liver suppressed curbed overproduction, contributing amelioration obese diabetic db/db mice. These results characterize as an important molecule upstream for regulating