The Common Marmoset as a Model for the Study of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis

摘要

Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome. The more clinically concerning form of the disease, nonalcoholic steatohepatitis (NASH), is characterized by steatosis, lobular inflammation, and ballooning degeneration. Here we describe a naturally occurring syndrome in the common marmoset that recapitulates the pathologic findings associated with NAFLD/NASH in humans. Hepatomegaly determined to result from NAFLD was observed in 33 of 183 marmosets. A comprehensive histopathologic assessment performed in 31 marmosets demonstrated that NAFLD was characterized by variably sized, Oil Red O staining cytoplasmic vacuoles and observed primarily in animals with evidence of obesity and insulin resistance. A subset of marmosets (16 of 31) also demonstrated evidence of NASH characterized by multifocal inflammation combined with ballooning hepatocellular degeneration. Marmosets with NASH demonstrated an increase in immunostaining with an antibody targeted against the human leukocyte antigens (HLA)-DP, HLA-DQ, and HLA-DR compared with marmosets without NASH (38.89 cells/10x field vs 12.05 cells/10x field, P = .05). In addition, marmosets with NASH demonstrated increased Ki-67 immunopositive cellular proliferation compared with those without (5.95 cells/10x field vs 1.53 cells/10x field, P = .0002). Finally, animals with NASH demonstrated significantly increased mean circulating serum iron levels (160.47 g/dl, P = .008) and an increase in numbers of Prussian blue-positive Kupffer cells (9.28 cells/40x field, P = .005) relative to marmosets without NASH (97.75 g/dl and 1.87 cells/40x, respectively). This study further characterizes the histopathology of NAFLD/NASH and suggests that the marmoset may be a valuable animal model with which to investigate the host and environmental factors contributing to the progression of NAFLD/ NASH.