Alcoholic liver disease (ALD) is one of the most common liver diseases in the United States and a major cause of chronic liver failure and mortality. The mechanisms of liver injury in ALD remain unclear and as a result there is no proven therapy for this disease. Critical to the development of ALD is an overactive hepatic innate immune response. Activated resident Kupffer cells and recruited macrophages generate soluble factors that lead to steatosis, hepatocellular injury and fibrosis. Recent findings indicat that alcohol promotes proinflammatory M1 rather than anti-inflammatory M2 macrophage polarization. Our prior investigations have identified novel functions for the lysosomal, degradative pathway of autophagy in the regulation of cellular signaling pathways and lipid metabolism that mediate M1 and M2 macrophage polarization. The objective of this proposal is to delineate mechanisms by which autophagy regulates macrophage polarization and the hepatic injury that occurs as the result of the overactive proinflammatory response in ALD. Preliminary findings demonstrate that steatosis and alcohol inhibit macrophage autophagy, and that ethanol and impaired autophagy act in concert to block M2 macrophage polarization. In addition, we have generated macrophage- specific mouse knockouts of autophagy and shown that they are sensitized to the development of a proinflammatory response and liver injury from lipopolysaccharide or ethanol. Based on these and other preliminary studies, our central hypothesis is that alcohol impairs macrophage autophagy which promotes proinflammatory macrophage polarization and activation leading to an overactive innate immune response and ALD. We will test this hypothesis in studies contained in three Specific Aims that will delineate the mechanism by which macrophage autophagy is decreased by alcohol, and how this effect alters macrophage polarization and the generation of a hepatic innate immune response to alcohol. First, we will test the hypothesis that alcohol decreases autophagic function in macrophages by inhibiting AMP-activated protein kinase signaling. Second, we will test the hypothesis that an alcohol-induced defect in autophagy promotes M1 and inhibits M2 macrophage polarization through effects on ER stress and mitochondrial ?-oxidation. Third, we will test the hypothesis that decreased autophagy in macrophages in vivo promotes ALD development by leading to an unrestrained proinflammatory immune response. The objective of these studies is to delineate novel paradigms by which the lysosomal pathway of autophagy regulates the hepatic proinflammatory innate immune response to alcohol. The ultimate goal of these investigations is to better understand the basic cellular mechanisms underlying the development of liver injury from alcohol in order to design new strategies to prevent and treat human ALD.

Public Health Relevance

Alcoholic liver disease (ALD) is one of the most prevalent liver diseases in the United States and a leading cause of chronic liver disease and mortality. The pathophysiology of this disease is unclear and as a result it has no established treatment. The objective of this proposal is to understand the mechanisms by which the hepatic immune response to alcohol is regulated by autophagy in order to delineate new therapeutic approaches for the prevention and cure of ALD.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
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Orosz, Andras
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Albert Einstein College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
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Amir, Muhammad; Czaja, Mark J (2018) Inflammasome-mediated inflammation and fibrosis: It is more than just the IL-1?. Hepatology 67:479-481
Cingolani, Francesca; Czaja, Mark J (2018) Oxidized Albumin-A Trojan Horse for p38 MAPK-Mediated Inflammation in Decompensated Cirrhosis. Hepatology 68:1678-1680
Shen, Yang; Czaja, Mark J (2018) A Novel Mechanism of Starvation-Stimulated Hepatic Autophagy: Calcium-Induced O-GlcNAc-Dependent Signaling. Hepatology :
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Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Czaja, Mark J (2016) Function of Autophagy in Nonalcoholic Fatty Liver Disease. Dig Dis Sci 61:1304-13
Singh, Saurav; Grabner, Alexander; Yanucil, Christopher et al. (2016) Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney Int 90:985-996
Cingolani, Francesca; Czaja, Mark J (2016) Regulation and Functions of Autophagic Lipolysis. Trends Endocrinol Metab 27:696-705
Czaja, Mark J (2015) A new mechanism of lipotoxicity: Calcium channel blockers as a treatment for nonalcoholic steatohepatitis? Hepatology 62:312-4

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