Role of Dietary Cholesterol in Alcoholic Steatohepatitis and Insulin Resistance

酒精滥用及其相关的慢性肝病在世界范围内引起高发病率和死亡率。流行病学数据表明，只有一部分重度饮酒者（约35%）会出现晚期肝损伤，这表明其他因素也会影响酒精相关性肝病（AALD）的发生和进展。最近的研究和我们的初步数据表明，饮食中的胆固醇与酒精相互作用，以修改进行性肝损伤。然而，胆固醇促进饮酒相关疾病进展的潜在机制在很大程度上缺乏。此外，酒精性脂肪性肝炎的特征是组织和全身炎症，这与胰岛素抵抗高度相关。然而，胆固醇在酒精相关的胰岛素抵抗中的作用仍然未知。有趣的是，据报道，胆固醇诱导肠道炎症，由于依折麦布对胆固醇吸收的抑制作用，依折麦布治疗可减轻肠道炎症。考虑到炎症在破坏肠屏障功能和肠-肝-轴在AALD发展中的关键作用，我们假设膳食胆固醇通过增加肠渗透性加剧AALD并损害胰岛素信号传导。此外，我们假设，通过阻断肠道胆固醇摄取，依折麦布治疗减弱了胆固醇和酒精对肠道屏障功能的累加效应，导致肝损伤减轻和胰岛素敏感性增强。因此，在具体目标1中，我们将仔细检查饲喂各种流质饲料（补充胆固醇或含依折麦布）的小鼠的肠道屏障功能。将检查跨细胞和细胞旁渗透性。在具体目标2中，我们将研究胆固醇在酒精相关胰岛素抵抗中的作用。我们推测，过量的胆固醇摄入会增强酒精喂养小鼠的胰岛素信号转导受损和葡萄糖代谢失调。然而，依折麦布治疗将减弱胆固醇和酒精对胰岛素抵抗的不良协同作用。这些拟议的研究将显著提高我们对膳食胆固醇作为调节酒精相关疾病进展的辅助因子的理解。此外，我们的研究结果将提供有价值的实验证据，依折麦布可能是一种治疗AALD和酒精相关代谢紊乱的治疗策略。

Alcohol abuse and its associated chronic liver disease cause high morbidity and mortality worldwide. The epidemiological data that only a portion of heavy drinkers (~35%) develops advanced liver injury indicates that other factors can affect the development and progression of alcohol-associated liver disease (AALD). Recent studies and our preliminary data have shown that dietary cholesterol interacts with alcohol to modify progressive liver damage. However, the underlying mechanism by which cholesterol promotes alcohol drinking-related disease progression is largely lacking. In addition, alcoholic steatohepatitis is characterized by tissue and systemic inflammation, which is highly associated with insulin resistance. However, the role of cholesterol in alcohol-associated insulin resistance remains unknown. Interestingly, it has been reported that cholesterol induces intestinal inflammation, which can be blunted by ezetimibe treatment due to its inhibitory effect on cholesterol absorption. Considering the critical role of inflammation in disrupting gut barrier function and the gut- liver-axis in the development of AALD, we hypothesize that dietary cholesterol exacerbates AALD and impairs insulin signaling by increasing intestinal permeability. Moreover, we hypothesize that, by blocking intestinal cholesterol uptake, ezetimibe treatment attenuates the additive effect of cholesterol and alcohol on gut barrier function, leading to reduced liver damage and enhanced insulin sensitivity. Therefore, in specific aim 1, we will carefully examine the gut barrier function in mice fed various liquid diets, either supplemented with cholesterol or containing ezetimibe. Both transcellular and paracellular permeability will be examined. In specific aim 2, we will investigate the role of cholesterol in alcohol-associated insulin resistance. We speculate that excessive cholesterol intake will potentiate the impaired insulin signaling and dysregulated glucose metabolism in alcohol-fed mice. However, ezetimibe treatment will blunt the adverse synergistic effects of cholesterol and alcohol on insulin resistance. These proposed studies will significantly enhance our understanding of dietary cholesterol as a cofactor in regulating alcohol-associated disease progression. Furthermore, our findings will provide valuable experimental evidence that ezetimibe could be a therapeutic strategy for the treatment of AALD and alcohol- related metabolic disorders.