Feeding a Western diet for 5 months, compared to a low fat control diet, resulted in 100% panlobular
macrosteatosis with some microvesicular steatosis, a 75% increase in peri-portal inflammation and 88% increase in lipogranuloma formation, and peri-portal and zone 1 sinusoidal fibrosis extending into zones 2 & 3 in places in 100% of the mice. When mice on a Western diet were treated with INT-767, there were marked and significant decreases in macrosteatosis (63%), microsteatosis Gefitinib (88%), inflammation (76%) and fibrosis (37%). These histopathological changes were accompanied by significant decreases in the lipogenic transcription factor SREBP-1c ( 25±1.4 in LF vs. 35±2.6 in WD, p<0.01 vs. 26±2.3 in WD+INT-767, p<0.05), pro-inflammatory mediator MCP-1(0.04±0.01 in LF vs. 0.38±0.07
in WD, p<0.01 vs. 0.11 ±0.04 in WD+INT-767, p<0.05), and profibrotic matrix protein Col1a1(2.4±0.6 in LF vs. 50±6.5 in WD, p<0.01 vs. 7.7±2.5 in WD+INT-767, p<0.01). The dual FXR-TGR5 agonist is therefore able to markedly and significantly arrest and revert progression of liver disease even when treatment is started in the presence of obesity, insulin resistance, and NAFLD/NASH. Disclosures: Luciano Adorini - Consulting: Intercept Pharmaceuticals Moshe Levi - Grant/Research Support: Intercept, Genzyme-Sanofi The following people have nothing to disclose: Xiaoxin Wang, Yuhuan Luo, Cherelle Parker, XL765 Rachel McMahan, Hugo R. Rosen, David J. Orlicky Excessive alcohol consumption leads to chronic alcoholic liver disease that ranges from fatty liver, to steatohepatitis, cirrhosis and in some cases hepatocellular carcinoma. Research evidence has suggested that elderly are more prone to severe liver injury due to excessive alcohol consumption, when compared to young adults. However, the mechanism is still unclear. We hypothesize Sinomenine that increased levels of neutrophils, which is a characteristic of human alcoholic liver disease can be affected by aging. Our current study uses female C57BL/6 mice from 18-month to 2 years of
age weighing from 20 g to 40g. These mice were fed with Lieber-DeCarli liquid diets containing eth-anol (5 % v/v) for 10 days, following a single ethanol binge (NIAAA model). Livery injury, demonstrated by elevated levels of alanine transaminase (ALT) and aspartate amino transfer-ase (AST) in middle age mice (18-month to 19-month) when compared to younger (6-month) or old mice (2 yr. old). The protocol used for chronic-plus-single-binge ethanol feeding induces, liver injury, inflammation and fatty liver, which mimic acute-on-chronic alcoholic liver injury in patients. Preliminary results from liver histological analysis revealed that there was a greater degree of steatosis and larger lipid droplets in eth-anol-fed livers from old mice when compared to the younger mice.