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首页> 外文期刊>Cell metabolism >Impaired generation of 12-hydroxylated bile acids links hepatic insulin signaling with dyslipidemia
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Impaired generation of 12-hydroxylated bile acids links hepatic insulin signaling with dyslipidemia

机译：12-羟基化胆汁酸生成受损将肝脏胰岛素信号传导与血脂异常联系起来

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The association of type 2 diabetes with elevated plasma triglyceride (TG) and very low-density lipoproteins (VLDL), and intrahepatic lipid accumulation represents a pathophysiological enigma and an unmet therapeutic challenge. Here, we uncover a link between insulin action through FoxO1, bile acid (BA) composition, and altered lipid homeostasis that brings new insight to this longstanding conundrum. FoxO1 ablation brings about two signature lipid abnormalities of diabetes and the metabolic syndrome, elevated liver and plasma TG. These changes are associated with deficiency of 12α-hydroxylated BAs and their synthetic enzyme, Cyp8b1, that hinders the TG-lowering effects of the BA receptor, Fxr. Accordingly, pharmacological activation of Fxr with GW4064 overcomes the BA imbalance, restoring hepatic and plasma TG levels of FoxO1-deficient mice to normal levels. We propose that generation of 12α-hydroxylated products of BA metabolism represents a signaling mechanism linking hepatic lipid abnormalities with type 2 diabetes, and a treatment target for this condition.
机译：2型糖尿病与血浆甘油三酸酯（TG）和极低密度脂蛋白（VLDL）升高以及肝内脂质蓄积的相关性代表了病理生理学难题和未得到满足的治疗挑战。在这里，我们揭示了通过FoxO1，胆汁酸（BA）成分和改变的脂质稳态之间的胰岛素作用之间的联系，这为这个长期存在的难题带来了新的见识。 FoxO1消融引起糖尿病和代谢综合征的两个标志性脂质异常，即肝脏和血浆TG升高。这些变化与缺乏12α-羟基化BA及其合成酶Cyp8b1有关，后者阻碍了BA受体Fxr降低TG的作用。因此，用GW4064激活Fxr的药理作用克服了BA的失衡，使FoxO1缺陷型小鼠的肝脏和血浆TG水平恢复到正常水平。我们建议，BA代谢的12α-羟基化产物的产生代表了将肝脂质异常与2型糖尿病相关联的信号传导机制，以及该病的治疗目标。

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