한빛사논문
- 조회3,014
Abstract
Hyo-Jung Kwon1,2,†, Young-Suk Won1,3,†, Ogyi Park1, Binxia Chang1, Michael J. Duryee4, Geoffrey E. Thiele4, Akiko Matsumoto5, Surendra Singh6, Mohamed A. Abdelmegeed7, Byoung-Joon Song7, Toshihiro Kawamoto8, Vasilis Vasiliou6, Geoffrey M. Thiele4, Bin Gao1,*
1 Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
2 College of Veterinary Medicine, Chungnam National University, Yuseong-gu, Daejeon, South Korea
3 Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, South Korea
4 Experimental Immunology Laboratory, Omaha VA Medical Center and the University of Nebraska Medical Center, Omaha, NE, USA
5Department of Social Medicine, Saga University School of Medicine, Saga, Japan
6 Department of Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA
7Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
8 Department of Environmental Health, University of Occupational and Environmental Health, Kitakyushu, Japan
†Dr. Hyo-Jung Kwon and Dr. Young-Suk Won contributed equally to this work.
*Corresponding author: Bin Gao, M.D., Ph.D., Laboratory of Liver Diseases, NIAAA/NIH, 5625 Fishers Lane, Bethesda, MD 20892.
Abstract
Aldehyde dehydrogenase 2 (ALDH2) is the major enzyme that metabolizes acetaldehyde produced from alcohol metabolism. Approximately 40?50% of East Asians carry an inactive ALDH2 gene and exhibit acetaldehyde accumulation after alcohol consumption. However, the role of ALDH2 deficiency in the pathogenesis of alcoholic liver injury remains obscure. In the present study, wild-type and ALDH2-/- mice were subjected to ethanol feeding and/or carbon tetrachloride (CCl4) treatment, and liver injury was assessed. Compared with wild-type mice, ethanol-fed ALDH2-/- mice had higher levels of malondialdehyde-acetaldehyde (MAA) adduct and greater hepatic inflammation, with higher hepatic IL-6 expression but surprisingly lower levels of steatosis and serum ALT. Higher IL-6 levels were also detected in ethanol-treated precision-cut-liver-slices from ALDH2-/- mice and in Kupffer cells isolated from ethanol-fed ALDH2-/- mice than those levels in wild-type mice. In vitro incubation with MAA enhanced the LPS-mediated stimulation of IL-6 production in Kupffer cells. In agreement with these findings, hepatic activation of the major IL-6 downstream signaling molecule signal transducer and activator of transcription 3 (STAT3) was higher in ethanol-fed ALDH2-/-mice than in wild-type mice. An additional deletion of hepatic STAT3 increased steatosis and hepatocellular damage in ALDH2-/- mice. Finally, ethanol-fed ALDH2-/- mice were more prone to CCl4-induced liver inflammation and fibrosis than ethanol-fed wild-type mice. Conclusions: ALDH2-/- mice are resistant to ethanol-induced steatosis but prone to inflammation and fibrosis via MAA-mediated paracrine activation of IL-6 in Kupffer cells. These findings suggest that alcohol, via acetaldehyde and its associated adducts, stimulates hepatic inflammation and fibrosis independent from causing hepatocyte death, and that ALDH2-deficient individuals may be resistant to steatosis and blood ALT elevation, but are prone to liver inflammation and fibrosis following alcohol consumption. (Hepatology 2014;)
Keywords: Acetaldehyde; ALDH2; ethanol; fibrosis; inflammation; IL-6; STAT3
논문정보
- Research article
- 2014년 02월 (BRIC 등록일 2014-02-07)
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