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858A AASLD ABSTRACTS HEPATOLOGY, October, 2015 BMI 29, 44% coffee users, 13% black tea users, 4% green tea users, mean ALT 26, mean AST 27, mean bilirubin 0.5 mg/ dL, mean albumin 3.8 mg/dL) were recruited. Apart from liver tests, cases and controls differed for age (P=0.046), education level (P=0.03), coffee use (P=0.0002). On a logistic regression analysis model after controlling for relevant co-variates, white race was associated with AH with OR (95% CI) of 5.5 (1.8-16.5). In contrast, odds of AH were lower by about 80% among coffee users; 0.21 (0.10-0.45). Recidivism was self-reported by 41 (16 cases) and 14 (6 cases) at 6 and 12 months respectively. On a logistic regression analysis model, low (
HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 859A intestinal crypts that are enriched in Paneth cells resulted in a dose- and time-dependent increase in IL-17 protein production. Conclusions: Our results highlight substantial hepatic immune cell changes due to alcohol and indicate that increased number of Paneth cells in the small intestine is an early event in alcohol-induced intestinal pathology. For the first time, we describe that IL-17 production by Paneth cells is induced by alcohol in small intestinal crypts and represents an early intestinal inflammatory marker in ALD. These observations identify a novel role of Paneth cells and intestinal IL-17 in ALD and highlight the importance of the gut-liver axis in alcoholic liver disease. Disclosures: The following authors have nothing to disclose: Benedek Gyongyosi, Patrick Lowe, Arvin Iracheta-Vellve, Abhishek Satishchandran, Aditya Ambade, Banishree Saha, Gyongyi Szabo 1319 Microbiota protects mice against acute alcohol-induced liver injury Peng Chen, Yukiko Miyamoto, Magdalena Mazagova, Lars Eckmann, Bernd Schnabl; University of California San Diego, La Jolla, CA Background: Chronic alcohol abuse is associated with intestinal bacterial overgrowth, increased intestinal permeability, and translocation of microbial products from the intestine to the portal circulation and liver. There is strong evidence that experimental alcoholic liver disease depends on translocated microbial products. The aim of our study was to investigate the physiological relevance of the intestinal microbiota in alcohol-induced liver injury using conventional and germ-free C57BL/6 mice. Methods: We employed germ-free mice in a model of acute alcohol exposure that mimics binge drinking. Acute alcoholic liver injury was induced by a single gavage of 300 μl of 30% (vol/vol) ethanol. Control mice were gavaged with an isocaloric amount of dextrose (300 μl, 0.42 g/ml). Mice were harvested 9 hours after gavage. Results: Germ-free mice showed significantly greater liver injury as determined by plasma ALT levels and H&E staining of liver sections after oral gavage of ethanol compared with conventional mice. This was accompanied by increased hepatic expression of macrophage and neutrophil markers. Several proinflammatory cytokines and chemokines including TNFα, Ccl2, Ccl4, Ccl5, Cxcl1, Cxcl2 and Cxcl5 were increased in alcohol-binged germ-free relative to conventional mice. In parallel, germ-free mice exhibited increased hepatic steatosis and upregulated expression of genes involved in fatty acid and triglyceride synthesis compared with conventional mice after acute ethanol administration. The absence of microbiota was also associated with increased hepatic expression of ethanol metabolizing enzymes, which led to faster ethanol elimination from the blood and lower plasma ethanol concentrations. In particular, hepatic Cyp2e1 gene and protein expression were significantly higher in germ-free mice before and after an alcohol binge. Furthermore, expression of aldehyde dehydrogenase 2 (Aldh2), which catalyzes the transformation of acetaldehyde to acetic acid, was significantly higher in control and alcohol challenged germ-free mice. Intestinal levels of ethanol metabolizing genes showed regional expression differences, and were overall higher in germ-free relative to conventional mice. In conclusion, our findings indicate that absence of the intestinal microbiota increases hepatic ethanol metabolism and the susceptibility to binge-like alcohol drinking. The commensal microbiota has therefore a beneficial role in protection against acute alcoholic liver disease. Disclosures: The following authors have nothing to disclose: Peng Chen, Yukiko Miyamoto, Magdalena Mazagova, Lars Eckmann, Bernd Schnabl 1320 Hepatocyte-specific StARD1 deletion attenuates alcoholic steatohepatitis Vicent Ribas 1,2 , Susana Nuñez 2,1 , Carmen Garcia-Ruiz 2,1 , Jose Fernandez-Checa 2,1 ; 1 Liver Unit, Hospital Clínic i Provincial de Barcelona, IDIBAPS, Barcelona, Spain; 2 Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC)), Barcelona, Spain Previous <strong>studies</strong> have shown that chronic alcohol feeding results in the depletion of mitochondrial GSH due to the accumulation of cholesterol in mitochondria. Mitochondrial GSH depletion stimulates reactive oxygen species and oxidative stress, and sensitizes hepatocytes to hypoxia and inflammatory cytokines-mediated apoptosis. Steroidogenic acute regulatory domain 1 (StARD1) protein was identified in steroidogenic tissues as a key protein responsible for cholesterol trafficking to the mitochondrial inner membrane for the synthesis of steroids. Mice with global StARD1 deletion die within 10 days due to adrenal lipoid hyperplasia. To circumvent this limitation, we generated mice with hepatocyte-specific deletion of StARD1 to study its role in alcoholic steatohepatitis induced by a novel model in which the Lieber DeCarli ethanol liquid diet was supplemented with 0.2% cholesterol. METHODS: We generated mice with floxP sites flanking exons 2-5 of StARD1 (floxed mice) and were crossed with Albumin-Cre transgenic mice. StARD1 liver-specific knockout animals (SLKO) and their corresponding StARD1 floxed control littermates were fed a Lieber DeCarli ethanol liquid diet supplemented with 0.2% cholesterol (L-C+Ch) for four weeks. At the end of this period, we determined parameters of liver damage, mitochondrial cholesterol and GSH homeostasis, markers of endoplasmic reticulum (ER) stress, inflammation, fibrosis and expression of lipogenic genes. RESULTS: In agreement with previous <strong>studies</strong>, StARD1 mRNA was induced by L-C+Ch feeding in StARD1 floxed animals (2-4 fold) while StARD1 expression was effectively ablated in SLKO liver. In parallel, L-C+Ch diet increased serum ALT (200-250U/L) in StARD1 floxed animals, an event that was significantly reduced by 50-60% in SLKO animals. Interestingly, total liver cholesterol was increased by L-C+Ch treatment in both genotypes, but mitochondrial cholesterol loading was increased only in StARD1 floxed animals. In line with this, SLKO liver mitochondria exhibited increased mGSH levels after L-C+Ch consumption, when compared to StARD1 floxed mice. Additionally, L-C+Ch feeding increased expression of ER stress markers (Chop, Atf6, Pdi), genes involved in lipogenesis (Srebp1, Srebp2, Dgat2, Fasn), fibrosis (Col1a1, Acta2) and inflammation (Ccl2, Tnfa, IL-6 and IL-1b) in StARD1 floxed mice (3-6 fold), whereas the rise in these markers was markedly attenuated (40-70%) in SLKO mice. CONCLUSIONS: These results suggest a key role of StARD1-mediated mitochondrial cholesterol trafficking in the pathogenesis of alcoholic steatohepatitis, indicating that StARD1 may be a novel target for the treatment of alcohol induced liver disease. Disclosures: The following authors have nothing to disclose: Vicent Ribas, Susana Nuñez, Carmen Garcia-Ruiz, Jose Fernandez-Checa
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1000A AASLD ABSTRACTS HEPATOLOGY, O
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1312A AUTHOR INDEX HEPATOLOGY, Octo
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1366A CATEGORY INDEX HEPATOLOGY, Oc
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