A high fat diet may kill regulatory T cells in the liver, allowing steatosis (simple fatty liver) to develop into steatohepatitis (fatty liver with inflammation), according to the results of a new study.
Nonalcoholic fatty liver disease (NAFLD), a condition related to obesity, can range in severity from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH) to cirrhosis which can lead to death. However, the progression of the disease is not well understood. The prevailing hypothesis suggests two-hits are necessary. The first is prolonged over-nutrition which causes the accumulation of fat in the liver. The second hit has been hypothesized to involve oxidative stress, mitochondrial injury or inflammatory cytokine production involving regulatory T cells (Tregs).
Tregs have recently emerged as a key player in hepatic immune regulation, so researchers, led by Xiong Ma of Johns Hopkins University in Baltimore, sought to determine their role in the pathogenesis of NASH. They hypothesized that regulation by Tregs is decreased in a fatty liver, which makes inflammation worse when the organ is exposed to secondary injury.
To test this hypothesis, they fed adult mice a high-fat diet to induce obesity, steatosis, and insulin resistance similar to that seen in humans. (Mice in the control group were fed a normal diet.) They examined the mice's hepatic lymphocyte population by flow cytometry. The researchers then injected the mice with liver inflammation-causing exogenous lipopolysaccarhide (LPS, a bacterial toxin usually presented in the normal intestine and carried to the liver by blood flow), and examined serum and liver tissue of the sacrificed mice.
They found that the hepatic Tregs gradually decreased during the administration of the high-fat diet and, at the end of 8 weeks, the levels were less than half of those in mice who ate a normal diet. The high-fat diet induced simple steatosis, and made the mice more susceptible to the LPS. Those on the high fat diet, who had depleted Tregs, sustained greater liver injury after they were exposed to the LPS.
"To our knowledge, this is the first time that Tregs have been linked to the inflammatory process in diet-induced steatosis," the authors report. Interestingly, they also found that the Treg depletion reversed itself when the mice were switched from a high-fat to a normal-fat diet.
"In conclusion, our study demonstrates that Tregs may play a critical role in controlling hepatic inflammation," the authors write. "We speculate that the depletion of Tregs may be the key event in the transition from simple steatosis to steatohepatitis." Their results also suggest that strategies aimed at increasing the number and/or function of Tregs should be explored to improve the prognosis of NAFLD.
Article: "A High-Fat Diet and Regulatory T Cells Influence Susceptibility to Endotoxin-Induced Liver Injury." Ma, Xiong; Hua, Jing; Mohamood, Abdiaziz; Hamad, Abdel; Ravi, Rajani; Li, Zhiping. Hepatology; November 2007; (DOI: 10.1002/hep.21823).
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