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.
Endocrinology. 2014 Apr;155(4):1255-67. doi: 10.1210/en.2013-1856. Epub 2014 Jan 17.
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.
过量产生富含甘油三酯的极低密度脂蛋白（VLDL-TG）是肥胖和 2 型糖尿病患者发生高甘油三酯血症的原因之一。为了了解其潜在机制，我们研究了叉头框 O6（FoxO6）对 VLDL-TG 产生的肝脏调节作用，FoxO6 是一种整合胰岛素信号与肝脏代谢的叉头转录因子。我们发现，表达组成型激活 FoxO6 等位基因的转基因小鼠发生高甘油三酯血症，最终导致 VLDL-TG 水平升高和餐后 TG 清除受损。这种效应部分是由于肝 VLDL-TG 产生增加所致。我们在培养的 HepG2 细胞和人原代肝细胞中重现了这些发现，证明 FoxO6 促进了肝 VLDL-TG 的分泌。这一作用与 FoxO6 刺激肝微粒体甘油三酯转移蛋白（MTP）产生的能力有关，MTP 是一种分子伴侣，催化 VLDL-TG 组装和分泌的限速步骤。FoxO6 被证明与 MTP 启动子结合，并刺激 HepG2 细胞中的 MTP 启动子活性。该效应被胰岛素抑制，这与胰岛素促进 FoxO6 磷酸化并使 FoxO6 DNA 结合活性失活的能力一致。在肥胖和 2 型糖尿病胰岛素抵抗小鼠中，FoxO6 的靶基因 MTP 启动子内的 FoxO6 结合位点发生突变，从而阻断了 FoxO6 介导的 MTP 启动子活性的诱导。胰岛素抵抗时肝 FoxO6 表达失调，抑制胰岛素抵抗肝脏中的 MTP 表达并抑制 VLDL-TG 过度产生，有助于改善肥胖和糖尿病 db/db 小鼠的高甘油三酯血症。这些结果表明 FoxO6 是调节肝 VLDL-TG 产生的 MTP 上游的重要信号分子。
