Non-alcoholic fatty liver disease is the most common reason for abnormal liver chemistries in the U.S. The factors that lead from benign steatosis to non-alcoholic steatohepatitis (NASH) are poorly understood. Transthyretin-Abcb11 (TTR-Abcb11) transgenic mice over-express the bile salt transporter Abcb11 and hypersecretes biliary lipids. Thus, the aim of this study is to employ feeding of the MCD diet to TTR-Abcb11 transgenic mice to further determine the mechanisms responsible for the development of steatohepatitis. FVB/NJ and TTR-Abcb11 mice were fed control or MCD diets for up to 30 days. Serum ALT levels, serum and hepatic triglyceride content, cytokines, markers of oxidative stress and expression of selective genes were examined. MCD diet fed TTR-Abcb11, but not wild type mice have elevated serum ALT levels compared after 7 days. They also have significantly lower hepatic triglyceride levels at all time points studied. After 14 days on the MCD diet, TTR-Abcb11 mice have 3 fold increases in TNF- mRNA and 3.9 fold increases in IL-6 mRNA compared to FVB/NJ mice. TTR-Abcb11 mice also had a greater increase in CYP2E1 expression. A greater decrease in SREBP-1c and fatty acid synthase mRNA expression was also seen in TTR-Abcb11 compared to wild type mice fed an MCD diet. They also have enhanced TNF-, IL-6 and CYP2E1 expression. We conclude that TTR-Abcb11 mice develop a more rapid hepatitis with less steatosis.