Submitted on January 23, 2008
Accepted on January 28, 2008
Mechanisms of steatohepatitis in mice fed a lipogenic methionine choline deficient (MCD) diet
Mary E. Rinella, Marc S. Elias, Robin R. Smolak, Tao Fu, Jayme Borensztajn, and Richard M. Green
Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
Corresponding Author: m-rinella{at}northwestern.edu
The methionine choline deficient (MCD) diet results in liver injury similar to human non-alcoholic steatohepatitis (NASH). The aims of this study were to define mechanisms of MCD-induced steatosis in insulin resistant db/db and insulin sensitive db/m mice. MCD fed db/db mice developed more hepatic steatosis and retained more insulin resistance than MCD fed db/m mice. Both subcutaneous and gonadal fat were reduced by MCD feeding; gonadal fat decreased by 23% in db/db mice and 90% in db/m mice. Weight loss was attenuated in the db/db mice, being only 13% compared to 35% in MCD fed db/db and db/m mice, respectively. Both strains had up-regulation of hepatic fatty acid transport proteins as well as increased hepatic uptake of 14C-oleic acid; 3-fold in db/m mice (p<0.001) and 2-fold in db/db mice (p<0.01) after 4 weeks of MCD feeding. In both murine strains, the MCD diet reduced triglyceride secretion and down-regulated genes involved in triglyceride synthesis. Therefore, increased fatty acid uptake and decreased VLDL secretion represent two important mechanisms by which the MCD diet promotes intrahepatic lipid accumulation in this model. Feeding the MCD diet to diabetic rodents broadens the applicability of this model for the study of human NASH.
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