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Intestinal Alkaline Phosphatase Prevents Acute Alcohol-Induced Liver Injury
Sulaiman R. Hamarneh1, MD, Kanakaraju Kalliannan1, MD, Mussa M. Rafat Mohamed1, MD, Palak Patel1, MD, Abeba Teshager1, MD, Nondita S. Malo1, MD, Seyed M. Abtahi1, MD, Nur Muhammad1, MD, Omeed Moaven1, MD, Atri Raychowdhury, MD, Sayeda N. Alam1, MD, Konstantinos P. Economopoulos1, MD, Atul K. Bhan2, MD, Madhu S. Malo1, MD, Richard A. Hodin1, MD
1Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 2Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA

Background: Bacterial endotoxin (LPS) plays a major role in the activation of Kupffer cells, production of inflammatory mediators and the pathogenesis of alcoholic liver injury. The brush-border enzyme intestinal alkaline phosphatase (IAP) dephosphorylates LPS, reduces endotoxemia and prevents LPS-induced inflammation. In this study, we sought to investigate whether oral IAP supplementation could protect against acute alcohol-induced liver injury. Methods: C57BL/6 female mice were treated with a single or multiple binge ethanol doses [6 or 5 g/kg body weight] by gastric gavage +/- pre-treatment, simultaneous treatment or post-treatment (n=5) with varying doses of IAP [100U or 200U/gavage]. Control mice were gavaged with dextran-maltose. Mice were sacrificed at different times and investigated. Results: In the single dose study, pretreatment with IAP resulted in significantly lower serum ALT than the ethanol group in a dose dependent fashion (38% inhibition with IAP 200U). Simultaneous-treatment with IAP (100U) also lowered serum ALT (EtOH vs. EtOH+simIAP= 1106.6 vs. 89.85.7U/L, p=0.04). In contrast, there was no beneficial impact in the post-treatment group. In the 3 dose study, pretreatment with IAP (200U) significantly lowered serum LPS (EtOH vs. EtOH+IAP= 2.10.35 vs. 1.00.21EU/ml, p=0.027), serum ALT (EtOH vs. EtOH+IAP=11416.1 vs. 68.96.7U/L, p=0.034) and protected against hepatic steatosis (EtOH vs. EtOH+IAP= 4 vs. 2, Hepatic Steatosis Score). Furthermore, liver TNF-alpha was also attenuated by IAP (EtOH vs. EtOH+IAP= 80.447.9 vs. 55.017.0 pg/mg protein, p=0.035). Conclusion: Treatment with Oral IAP protected mice from acute alcohol-induced hepatotoxicity and steatosis. Oral IAP supplementation could represent a novel therapy to prevent against alcoholic liver disease in humans.


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