Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
J Clin Invest. 2018 Apr 2;128(4):1615-1626. doi: 10.1172/JCI94230. Epub 2018 Mar 19.
Insulin resistance and type 2 diabetes are associated with low levels of high-density lipoprotein cholesterol (HDL-C). The insulin-repressible FoxO transcription factors are potential mediators of the effect of insulin on HDL-C. FoxOs mediate a substantial portion of insulin-regulated transcription, and poor FoxO repression is thought to contribute to the excessive glucose production in diabetes. In this work, we show that mice with liver-specific triple FoxO knockout (L-FoxO1,3,4), which are known to have reduced hepatic glucose production, also have increased HDL-C. This was associated with decreased expression of the HDL-C clearance factors scavenger receptor class B type I (SR-BI) and hepatic lipase and defective selective uptake of HDL cholesteryl ester by the liver. The phenotype could be rescued by re-expression of SR-BI. These findings demonstrate that hepatic FoxOs are required for cholesterol homeostasis and HDL-mediated reverse cholesterol transport to the liver.
胰岛素抵抗和 2 型糖尿病与高密度脂蛋白胆固醇 (HDL-C) 水平降低有关。胰岛素抑制型 FoxO 转录因子是胰岛素对 HDL-C 作用的潜在介质。FoxOs 介导了胰岛素调节转录的大部分，而 FoxO 抑制不良被认为导致了糖尿病中葡萄糖产生的过度。在这项工作中，我们表明，肝脏特异性三重 FoxO 敲除 (L-FoxO1,3,4) 的小鼠，已知其肝葡萄糖生成减少，也具有增加的 HDL-C。这与 HDL-C 清除因子清道夫受体 B 类 I (SR-BI) 和肝脂肪酶的表达降低以及肝脏对 HDL 胆固醇酯的选择性摄取缺陷有关。该表型可以通过重新表达 SR-BI 来挽救。这些发现表明，肝 FoxOs 是胆固醇稳态和 HDL 介导的胆固醇逆转运到肝脏所必需的。
