LRH-1-dependent glucose sensing determines intermediary metabolism in liver
LRH-1-dependent glucose sensing determines intermediary metabolism in liver
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DOI：
10.1172/jci62368
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发表时间：
2012-08-01
影响因子：
15.9
通讯作者：
Schoonjans, Kristina
中科院分区：
文献类型：
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作者：
Oosterveer, Maaike H.;Mataki, Chikage;Schoonjans, Kristina
肝受体同源物1（LRH-1）是胆固醇和胆汁酸稳态的既定调节剂，最近已成为肝脏疾病的潜在药物靶点。虽然LRH-1的激活可以保护肝脏免受饮食诱导的脂肪变性和胰岛素抵抗，但对LRH-1在生理条件下如何控制肝脏葡萄糖和脂肪酸代谢知之甚少。因此，我们评估了LRH-1在肝脏中间代谢中的作用。在肝脏中Lrhl条件性缺失的小鼠中，肝脏葡萄糖通量的分析显示与野生型同窝出生小鼠相比，葡萄糖激酶（GCK）和糖原合酶通量减少。这些变化归因于LRH-1对Gck的直接转录调控。在LRH-1缺乏的肝脏中，受损的葡萄糖激酶介导的葡萄糖磷酸化也与糖原合成减少、糖酵解和新生脂肪生成有关，这是对急性和长期葡萄糖暴露的反应。因此，这些动物的肝脏碳水化合物反应元件结合蛋白活性降低。累积起来，这些数据确定LRH-1作为肝葡萄糖传感系统的关键调节成分，需要适当整合餐后葡萄糖和脂质代谢。
Liver receptor homolog 1 (LRH-1), an established regulator of cholesterol and bile acid homeostasis, has recently emerged as a potential drug target for liver disease. Although LRH-1 activation may protect the liver against diet-induced steatosis and insulin resistance, little is known about how LRH-1 controls hepatic glucose and fatty acid metabolism under physiological conditions. We therefore assessed the role of LRH-1 in hepatic intermediary metabolism. In mice with conditional deletion of Lrhl in liver, analysis of hepatic glucose fluxes revealed reduced glucokinase (GCK) and glycogen synthase fluxes as compared with those of wild-type littermates. These changes were attributed to direct transcriptional regulation of Gck by LRH-1. Impaired glucokinase-mediated glucose phosphorylation in LRH-1-deficient livers was also associated with reduced glycogen synthesis, glycolysis, and de novo lipogenesis in response to acute and prolonged glucose exposure. Accordingly, hepatic carbohydrate response element-binding protein activity was reduced in these animals. Cumulatively, these data identify LRH-1 as a key regulatory component of the hepatic glucose-sensing system required for proper integration of postprandial glucose and lipid metabolism.