Obese Mice Are More Susceptible To Liver Abnormalities

NKT cells originate in the thymus but accumulate in the liver wherethey regulate the production of cytokines (cell proteins). A previousstudy of leptin-deficient obese mice noted depleted levels of NKTcells. However, since obese humans have increased leptin levels, theresearchers were not sure if their findings in mice were relevant tohuman fatty liver disease. To address this question, they studied a newdiet-induced model of non-alcoholic fatty liver disease.

The researchers, led by Zhiping Li of Johns Hopkins Universityin Baltimore, obtained wild-type mice and fed them commercial dietswith different nutritional contents for four to twelve weeks. The micewere then sacrificed to obtain liver and serum tissue. The researchersisolated hepatic mononuclear cells, which they then incubated andevaluated by flow cytometry. They also isolated total hepatic RNA foranalysis. Finally, they measured levels of serum alanineaminotransferases (ALT), a marker of liver injury.

The mice on high fat diets gained significantly more weightthan the mice on normal diets, and they also developed fatty livers.Their hepatic mononuclear cells revealed significantly fewer hepaticCD4+ NKT cells. Subsequent tests revealed doubled production of IL-12,a cytokine that reduces NKT cell viability, as well as increased NKTcell death.

"Preliminary studies suggest that hepatic NKT cell numbersremain constant before high fat-fed mice develop significant steatosisafter consuming the high fat diet for one week," the authors report."However, more studies are needed to better understand the temporalrelationship between development of steatosis and NKT cell depletion."

The results also showed that high fat diets increased theproduction of hepatic pro-inflammatory cytokine. When the researchersinduced liver injury in mice on the varying diets, they found that highfat-diet mice experienced more inflammation and necrosis thannormal-diet mice.

This study shows that high-fat diets correlate to a chronicinflammatory 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 localproduction of pro- and anti-inflammatory cytokines.

"Further evaluation of other mouse strains, different agegroups and genders will be necessary to clarify if any of these factorsmodulate susceptibility to diet-related changes in hepatic NKT cells,"the authors say.

"Nevertheless," they conclude, "our findings are importantbecause they clearly demonstrate significant dietary effects on'classic' NKT cells and cytokine production by other liver mononuclearcells."

Article: "Dietary Factors Alter Hepatic Innate Immune System in Micewith Non-Alcoholic Fatty Liver Disease." Zhiping Li, Mark J. Soloski,and Anna Mae Diehl, Hepatology; October 2005; (DOI: 10.1002/hep.20826).