Role of Dietary Cholesterol in Alcoholic Steatohepatitis and Insulin Resistance

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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.