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Intestinal Alkaline Phosphatase Attenuates Alcohol-Induced Hepatosteatosis in Mice

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Abstract

Background and Aims

Bacterially derived factors from the gut play a major role in the activation of inflammatory pathways in the liver and in the pathogenesis of alcoholic liver disease. The intestinal brush-border enzyme intestinal alkaline phosphatase (IAP) detoxifies a variety of bacterial pro-inflammatory factors and also functions to preserve gut barrier function. The aim of this study was to investigate whether oral IAP supplementation could protect against alcohol-induced liver disease.

Methods

Mice underwent acute binge or chronic ethanol exposure to induce alcoholic liver injury and steatosis ± IAP supplementation. Liver tissue was assessed for biochemical, inflammatory, and histopathological changes. An ex vivo co-culture system was used to examine the effects of alcohol and IAP treatment in regard to the activation of hepatic stellate cells and their role in the development of alcoholic liver disease.

Results

Pretreatment with IAP resulted in significantly lower serum alanine aminotransferase compared to the ethanol alone group in the acute binge model. IAP treatment attenuated the development of alcohol-induced fatty liver, lowered hepatic pro-inflammatory cytokine and serum LPS levels, and prevented alcohol-induced gut barrier dysfunction. Finally, IAP ameliorated the activation of hepatic stellate cells and prevented their lipogenic effect on hepatocytes.

Conclusions

IAP treatment protected mice from alcohol-induced hepatotoxicity and steatosis. Oral IAP supplementation could represent a novel therapy to prevent alcoholic-related liver disease in humans.

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Acknowledgments

Richard A. Hodin was supported by National Institute of Health grant NIH/NIDDK T32 (No. DK007754), The Ellison Foundation grant and Nutritional Obesity Research Center of Harvard (NORCH) NIH (No. P30-DK040561). We also thank the animal facility and the pathology lab at MGH for maintainance of animals and preparation of tissue sections.

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    Authors and Affiliations

    1. Department of Surgery, Harvard Medical School, Massachusetts General Hospital, 15 Parkman Street, Boston, MA, 02114, USA

      Sulaiman R. Hamarneh, Kanakaraju Kaliannan, Sara A. Morrison, Tyler J. Tantillo, Qingsong Tao, Mussa M. Rafat Mohamed, Juan M. Ramirez, Aaron Karas, Wei Liu, Dong Hu, Abeba Teshager, Sarah Shireen Gul, Konstantinos P. Economopoulos, Madhu S. Malo & Richard A. Hodin

    2. Gastrointestinal Unit, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA

      Byeong-Moo Kim & Michael Y. Choi

    3. Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, 02114, USA

      Atul K. Bhan

    4. Harvard Stem Cell Institute, Cambridge, MA, 02138, USA

      Michael Y. Choi

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    1. Sulaiman R. Hamarneh
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    Contributions

    RAH, MYC, MSM, SRH, and BK contributed to study concept and theory; RAH, MYC, SRH, and BK contributed to research design; SRH, BK, KK, SAM, TJT, QT, MMRM, JMR, AK, WL, DH, AT, SSG, KPE, AKB, MSM, MYC, and RAH contributed to data acquisition; SRH, BK, KK, SAM, TJT, QT, MMRM, JMR, AK, WL, DH, AT, SSG, KPE, AKB, MSM, MYC, and RAH contributed to data analyses and interpretation; SRH, BK, SAM, KPE, MYC, and RAH contributed to statistical analyses; SRH, BK, CYM, and RAH contributed to drafting of the manuscript; all authors contributed to critical review of the manuscript for important intellectual content; RAH obtained funding; all authors contributed to approval of the manuscript; RAH and MYC supervised the study.

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    Correspondence to Michael Y. Choi or Richard A. Hodin.

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    Sulaiman R. Hamarneh and Byeong-Moo Kim have contributed equally to this work.

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    Hamarneh, S.R., Kim, BM., Kaliannan, K. et al. Intestinal Alkaline Phosphatase Attenuates Alcohol-Induced Hepatosteatosis in Mice. Dig Dis Sci 62, 2021–2034 (2017). https://doi.org/10.1007/s10620-017-4576-0

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