A Role of Hypothalamic Dysfunction in Alcoholic Liver Disease

胰岛素抵抗是酒精性肝病的重要危险因素。反之亦然，重酒 消费导致胰岛素抵抗，与肝纤维化的进展有关 非酒精性脂肪肝(NAFLD)。胰岛素是调节血脂和血糖的关键荷尔蒙 新陈代谢；它也是炎症的重要调节因素。因此，肝脏胰岛素的作用可能是一个关键。 在ALD的发病机制中扮演了重要角色，但胰岛素作用受损导致发病的机制 对于ALD仍然知之甚少。我们和其他人之前已经证明，体内的胰岛素信号 下丘脑内侧基底核(MBH)控制肝脏葡萄糖的产生(HGP)，密度很低 脂蛋白(VLDL)分泌，白色脂肪组织(WAT)脂解和天然免疫通过 植物性神经系统。根据我们的试验数据显示，在狂饮的大鼠模型中， 即短期饮酒会损害葡萄糖耐量并诱导胰岛素抵抗，这是由于 肝脏胰岛素作用受损。酗酒显著损害下丘脑的胰岛素作用，其定义为 下丘脑胰岛素抑制HGP和脂肪组织脂解的能力。因此，主要的假设是 这项提案中提出的一些由酒精引起的代谢和先天免疫缺陷是 这是由于大脑的作用扰乱了新陈代谢和先天免疫的自主控制。在……里面 支持这一新范式的我们发现，下丘脑胰岛素作用受损的一个中心原因是 下丘脑中胰岛素信号的减少可能是由于炎症、内质网应激和 胰岛素信号负调控蛋白酪氨酸磷酸酶L b的表达。在这里我们 建议描绘长期饮酒损害胰岛素作用的机制， 扰乱肝脏碳水化合物、氨基酸和脂肪代谢，并产生促炎作用 肝脏内易患ALD的环境。

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.