Role of Dietary Cholesterol in Alcoholic Steatohepatitis and Insulin Resistance

膳食胆固醇在酒精性脂肪性肝炎和胰岛素抵抗中的作用

• 批准号: 10040154
• 负责人: Lin Jia
• 金额: $ 7.71万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10040154
• 关键词: Adverse effects; Affect; Alcohol abuse; Alcohol consumption; Alcoholic beverage heavy drinker; Alcoholic liver damage; Alcoholic steatohepatitis; Alcohols; Attenuated; Cell Death; Cessation of life; Cholesterol; Chronic; Data; Development; Diet; Dietary Cholesterol; Dietary Supplementation; Disease; Disease Progression; Enterocytes; Epithelial; Extravasation; Fatty acid glycerol esters; Glucose Intolerance; Health; Heavy Drinking; Hepatic; Human; Impairment; Incidence; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Intake; Intestinal permeability; Intestines; Lead; Lipopolysaccharides; Liquid substance; Liver; Liver diseases; Metabolic; Metabolic Diseases; Metabolic dysfunction; Molecular; Morbidity - disease rate; Mus; NOS2A gene; Nutritional; Obesity; Permeability; Plasma; Publications; Reporting; Rodent; Role; Severities; Steatohepatitis; TLR4 gene; Testing; Therapeutic; Tight Junctions; Tissues; United States; alcohol abuse therapy; blood glucose regulation; cholesterol absorption; chronic liver disease; cofactor; disability; epidemiologic data; experimental study; ezetimibe; fatty acid-binding proteins; feeding; glucose metabolism; glucose tolerance; gut-liver axis; hypercholesterolemia; improved; inflammatory disease of the intestine; inhibitor/antagonist; insulin sensitivity; insulin signaling; insulin tolerance; liver injury; mRNA Expression; mortality; non-alcoholic fatty liver disease; novel therapeutic intervention; systemic inflammatory response; treatment strategy; uptake

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.

酗酒及其相关的慢性肝病导致全世界的高发病率和死亡率。流行病学数据显示，只有一部分重度饮酒者（约35%）出现晚期肝损伤，这表明其他因素也可能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，膳食胆固醇与酒精相互作用，可以改变进行性肝损伤。然而，胆固醇促进饮酒相关疾病进展的潜在机制尚不清楚。此外，酒精性脂肪性肝炎的特点是组织和全身炎症，这与胰岛素抵抗高度相关。然而，胆固醇在酒精相关胰岛素抵抗中的作用仍不清楚。有趣的是，据报道，胆固醇会引起肠道炎症，而依折麦布治疗可以减轻肠道炎症，因为它对胆固醇吸收有抑制作用。考虑到炎症在破坏肠道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会加剧 AALD，并通过增加肠道通透性来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，从而减少肝损伤并增强胰岛素敏感性。因此，在具体目标 1 中，我们将仔细检查饲喂各种流质饮食（补充胆固醇或含有依折麦布）的小鼠的肠道屏障功能。将检查跨细胞和旁细胞渗透性。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加剧酒精喂养小鼠的胰岛素信号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利协同作用。这些拟议的研究将显着增强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，表明依折麦布可能成为治疗 AALD 和酒精相关代谢紊乱的治疗策略。