Immunologic Mechanisms of Alcoholic Liver Disease

Gao, Bin

Abstract

Our laboratory has been actively studying the pathogenesis of alcoholic liver disease, focusing on how alcohol attenuates T-cell metabolism and hepatitis in ALDH2-deficient mice and humans. Alcohol inhibits T-cell glucose metabolism and hepatitis in ALDH2-deficient mice and humans: Roles of acetaldehyde and glucocorticoids Objective: Aldehyde dehydrogenase 2 (ALDH2), a key enzyme to detoxify acetaldehyde in the liver, exists in both active and inactive forms in humans. Individuals with inactive ALDH2 accumulate acetaldehyde after alcohol consumption. However, how acetaldehyde affects T-cell hepatitis remains unknown. Design: Wild-type and Aldh2-/- mice were subjected to chronic ethanol feeding and concanavalin A (ConA)-induced T-cell hepatitis. Effects of acetaldehyde on T-cell glucose metabolism were investigated in vitro. Human subjects were recruited for acute alcohol drinking and plasma cortisol and corticosterone measurement. Results: Ethanol feeding exacerbated ConA-induced hepatitis in wild-type mice but surprisingly attenuated it in Aldh2-/- mice despite higher acetaldehyde levels in Aldh2-/- mice. Elevation of serum cytokines and their downstream signals in the liver post ConA injection was attenuated in ethanol-fed Aldh2-/- mice compared to wild-type mice. In vitro exposure to acetaldehyde inhibited ConA-induced production of several cytokines without affecting their mRNAs in mouse splenocytes. Acetaldehyde also attenuated IFN- production in phytohemagglutinin-stimulated human peripheral lymphocytes. Mechanistically, acetaldehyde interfered with glucose metabolism in T cells by inhibiting aerobic glycolysis-related signal pathways. Finally, compared to wild-type mice, ethanol-fed Aldh2-/- mice had higher levels of serum corticosterone, a well-known factor that inhibits aerobic glycolysis. Blockade of corticosterone partially restored ConA-mediated hepatitis in ethanol-fed Aldh2-/- mice. Acute alcohol drinking elevated plasma cortisol and corticosterone levels in human subjects with higher levels in those with inactive ALDH2 than those with active ALDH2. Conclusions: ALDH2 deficiency is associated with elevated acetaldehyde and glucocorticoids post alcohol consumption, thereby inhibiting T-cell activation and hepatitis

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Type: Investigator-Initiated Intramural Research Projects (ZIA)
• Project #: 1ZIAAA000369-17
• Application #: 9771172
• Support Year: 17
• Fiscal Year: 2018

Institution

• Name: Alcohol Abuse and Alcoholism

Publications

Ouyang, Xinshou; Han, Sheng-Na; Zhang, Ji-Yuan et al. (2018) Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1? Transactivation in Steatohepatitis. Cell Metab 27:1156

Alves-Paiva, Raquel M; Kajigaya, Sachiko; Feng, Xingmin et al. (2018) Telomerase enzyme deficiency promotes metabolic dysfunction in murine hepatocytes upon dietary stress. Liver Int 38:144-154

Ouyang, Xinshou; Han, Sheng-Na; Zhang, Ji-Yuan et al. (2018) Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1? Transactivation in Steatohepatitis. Cell Metab 27:339-350.e3

Gao, Bin; Xiang, Xiaogang (2018) Interleukin-22 from bench to bedside: a promising drug for epithelial repair. Cell Mol Immunol :

Chen, Hanqing; Shen, Feng; Sherban, Alex et al. (2018) DEP domain-containing mTOR-interacting protein suppresses lipogenesis and ameliorates hepatic steatosis and acute-on-chronic liver injury in alcoholic liver disease. Hepatology 68:496-514

Guillot, Adrien; Gasmi, Imène; Brouillet, Arthur et al. (2018) Interleukins-17 and 27 promote liver regeneration by sequentially inducing progenitor cell expansion and differentiation. Hepatol Commun 2:329-343

Li, Hongjie; Feng, Dechun; Cai, Yan et al. (2018) Hepatocytes and neutrophils cooperatively suppress bacterial infection by differentially regulating lipocalin-2 and neutrophil extracellular traps. Hepatology 68:1604-1620

Jiang, Yiming; Feng, Dechun; Ma, Xiaochao et al. (2018) Pregnane X Receptor Regulates Liver Size and Liver Cell Fate via Yes-associated Protein Activation. Hepatology :

Li, Man; He, Yong; Zhou, Zhou et al. (2017) MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6-p47phox-oxidative stress pathway in neutrophils. Gut 66:705-715

He, Yong; Gao, Bin (2017) A small specific-sized hyaluronic acid ameliorates alcoholic liver disease by targeting a small RNA: New hope for therapy? Hepatology 66:321-323