Steatohepatitis develops rapidly in transgenic mice overexpressing Abcb11 and fed a methionine-choline-deficient diet.
Nonalcoholic fatty liver disease is the most common reason for abnormal liver chemistries in the United States. The factors that lead from benign steatosis to nonalcoholic steatohepatitis are poorly understood. Transthyretin-Abcb11 (TTR-Abcb11) transgenic mice overexpress the bile salt transporter Abcb11 and hypersecrete biliary lipids. Thus the aim of this study is to employ feeding of the methionine-choline-deficient (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 aminotransferase 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 aminotransferase levels when 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-alpha mRNA and 3.9-fold increases in IL-6 mRNA compared with FVB/NJ mice. TTR-Abcb11 mice also had a greater increase in cytochrome P-450 2E1 expression. A greater decrease in sterol regulatory element binding protein-1c and fatty acid synthase mRNA expression was also seen in TTR-Abcb11 compared with wild-type mice fed an MCD diet. They also have enhanced TNF-alpha, IL-6, and cytochrome P-450 2E1 expression. We conclude that TTR-Abcb11 mice develop a more rapid hepatitis with less steatosis.
Sundaram
Shikha S
SS
Division of Gastroenterology and Hepatology and Nutrition, Departments of Pediatrics, Department of Internal Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Whitington
Peter F
PF
Green
Richard M
RM
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000494:pharmacology; D000818:Animals; D002796:Choline Deficiency / Q000150:complications* / Q000662:veterinary; D019392:Cytochrome P-450 CYP2E1 / Q000494:pharmacology; D004032:Diet; D005234:Fatty Liver / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008715:Methionine / Q000172:deficiency*; D051379:Mice; D008822:Mice, Transgenic; D011228:Prealbumin / Q000235:genetics* / Q000494:pharmacology
C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D011228:Prealbumin; D008715:Methionine; D019392:Cytochrome P-450 CYP2E1