Mice that were fed diets high in fat and sugar developed immune system abnormalities in their livers, including reduced numbers of natural killer T (NKT) cells. These diet-related changes may contribute to obesity-related liver disease, according to a new study.
The study is published in the October 2005 issue of Hepatology, the official journal of the American Association for the Study of Liver Diseases (AASLD). Published by John Wiley & Sons, Inc., Hepatology is available online via Wiley InterScience.
NKT cells originate in the thymus but accumulate in the liver where they regulate the production of cytokines (cell proteins). A previous study of leptin-deficient obese mice noted depleted levels of NKT cells. However, since obese humans have increased leptin levels, the researchers were not sure if their findings in mice were relevant to human fatty liver disease. To address this question, they studied a new diet-induced model of non-alcoholic fatty liver disease.
The researchers, led by Zhiping Li of Johns Hopkins University in Baltimore, obtained wild-type mice and fed them commercial diets with different nutritional contents for four to twelve weeks. The mice were then sacrificed to obtain liver and serum tissue. The researchers isolated hepatic mononuclear cells, which they then incubated and evaluated by flow cytometry. They also isolated total hepatic RNA for analysis. Finally, they measured levels of serum alanine aminotransferases (ALT), a marker of liver injury.
The mice on high fat diets gained significantly more weight than the mice on normal diets, and they also developed fatty livers. Their hepatic mononuclear cells revealed significantly fewer hepatic CD4+ NKT cells. Subsequent tests revealed doubled production of IL-12, a cytokine that reduces NKT cell viability, as well as increased NKT cell death.
"Preliminary studies suggest that hepatic NKT cell numbers remain constant before high fat-fed mice develop significant steatosis after consuming the high fat diet for one week," the authors report. "However, more studies are needed to better understand the temporal relationship between development of steatosis and NKT cell depletion."
The results also showed that high fat diets increased the production of hepatic pro-inflammatory cytokine. When the researchers induced liver injury in mice on the varying diets, they found that high fat-diet mice experienced more inflammation and necrosis than normal-diet mice.
This study shows that high-fat diets correlate to a chronic inflammatory state in the liver, which promotes chronic liver disease. The researchers suggest a potential mechanism for this outcome: diet-induced depletion of the hepatic NKT cells that balance local production of pro- and anti-inflammatory cytokines.
"Further evaluation of other mouse strains, different age groups and genders will be necessary to clarify if any of these factors modulate susceptibility to diet-related changes in hepatic NKT cells," the authors say.
"Nevertheless," they conclude, "our findings are important because they clearly demonstrate significant dietary effects on 'classic' NKT cells and cytokine production by other liver mononuclear cells."