A Role of Hypothalamic Dysfunction in Alcoholic Liver Disease

胰岛素抵抗是酒精性肝病（ALD）的重要危险因素。反之亦然，重酒精 消耗诱导胰岛素抵抗，与肝纤维化进展相关， 非酒精性脂肪肝（NAFLD）。胰岛素是调节血脂和血糖的关键激素 代谢;它也是炎症的重要调节剂。因此，肝胰岛素作用可能是一个关键， 在ALD的发病机制中起作用，然而，受损的胰岛素作用倾向于 对ALD的了解仍然很少。我们和其他人先前已经证明， 下丘脑内侧基底核（MBH）控制肝葡萄糖生成（hGP），密度极低 脂蛋白（VLDL）分泌、白色脂肪组织（WAT）脂解和通过 自主神经系统。根据我们的初步数据，表明在一个酗酒的大鼠模型中， 即短期饮酒会损害葡萄糖耐量并诱导胰岛素抵抗， 肝脏胰岛素作用受损。酗酒明显损害下丘脑胰岛素作用，定义为 下丘脑胰岛素抑制hGP和脂肪组织脂解的能力。因此，主要假设 在这个建议中提出的是，酒精引起的一些代谢和先天免疫缺陷是 这是由于大脑的影响破坏了新陈代谢和先天免疫的自主控制。在 我们发现下丘脑胰岛素作用受损的一个主要原因是 下丘脑中胰岛素信号传导减少，可能是由于炎症增加，ER应激和 蛋白酪氨酸磷酸酶I B（PTPI B）的表达，其是胰岛素信号传导的负调节剂。这里我们 建议描述慢性饮酒损害胰岛素作用的机制， 破坏肝脏碳水化合物、氨基酸和脂质代谢， 肝脏内的环境容易导致ALD。

Insulin resistance is an important risk factor for alcoholic liver disease (ALD). Vice versa, heavy alcohol consumption induces insulin resistance that is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD). Insulin is the key hormone that regulates lipid and glucose metabolism; it is also an important regulator of inflammation. Thus, hepatic insulin action is likely a key player in the pathogenesis of ALD, yet the mechanisms through which impaired insulin action predisposes to ALD remain poorly understood. We and others have previously demonstrated that insulin signaling within the mediobasal hypothalamus (MBH) controls hepatic glucose production (hGP), very low density lipoprotein (VLDL) secretion, white adipose tissue (WAT) lipolysis and innate immunity through the autonomic nervous system. Based on our pilot data that demonstrate that in a rat model for binge drinking, i.e. short term alcohol consumption impairs glucose tolerance and induces insulin resistance that is due to impaired hepatic insulin action. Binge drinking markedly impairs hypothalamic insulin action, defined as the ability of hypothalamic insulin to suppress hGP and adipose tissue lipolysis. Thus, the major hypothesis proposed in this proposal is that some of the metabolic and innate immunity defects induced by alcohol are caused through brain effects disrupting autonomic control of both metabolism and innate immunity. In support ofthis novel paradigm we find that a central cause ofthe impaired hypothalamic insulin action is decreased insulin signaling in the hypothalamus likely due to increased inflammation, ER stress and expression of protein tyrosine phosphatase l b (PTPIb), a negative regulator of insulin signaling. Here we propose to delineate the mechanisms through which chronic alcohol consumption impairs insulin action, disrupts hepatic carbohydrate, amino acid and lipid metabolism and generates a pro-inflammatory environment within the liver that predisposes to ALD.