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.

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Chronic alcohol consumption can cause alcoholic liver disease (ALD). In this proposal we aim to investigate the role of the neurotoxic effects of alcohol in impairing hepatic metabolism and if a prevention of the brain effects of alcohol can prevent liver disease. These studies will advance our understanding of how alcoholism leads to ALD and may identify strategies to prevent ALD.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Special Emphasis Panel (ZAA1-GG (50))
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Orosz, Andras
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Icahn School of Medicine at Mount Sinai
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Howarth, Deanna L; Lindtner, Claudia; Vacaru, Ana M et al. (2014) Activating transcription factor 6 is necessary and sufficient for alcoholic fatty liver disease in zebrafish. PLoS Genet 10:e1004335