A high-fat diet and regulatory T cells influence susceptibility to endotoxin-induced liver injury.
In nonalcoholic fatty liver disease, the pathogenesis of progression from simple steatosis to steatohepatitis has not been fully clarified. Many factors, including oxidative stress and hepatic immune regulation, contribute to the inflammation in steatosis. Because regulatory T cells (Tregs) are important components of immune regulation, we have now investigated their role in the pathogenesis of nonalcoholic steatohepatitis. Wild-type C57BL/6 mice were fed a high-fat (HF) diet to induce steatosis, and the hepatic lymphocyte population was analyzed by flow cytometry. HF-induced steatosis was associated with the depletion of hepatic Tregs and led to up-regulation of the inflammatory tumor necrosis factor-alpha signaling pathway. When challenged by exogenous lipopolysaccharide, the HF-fed mice developed liver inflammation. In contrast, the adoptive transfer of Tregs decreased inflammation in HF-fed mice. In comparison with effector T cells, Tregs had a lower expression of Bcl-2 and, therefore, increased susceptibility to oxidative stress-induced apoptosis. The treatment of mice with the antioxidant Mn(III)tetrakis(4-benzoic acid)porphyrin chloride reduced Treg apoptosis, increased the number of hepatic Tregs, and decreased hepatic inflammation in HF-fed mice.


CONCLUSIONS
Our results indicate that increased oxidative stress in a fatty liver causes the apoptosis of Tregs, reduces the number of hepatic Tregs, and leads to a lowered suppression of inflammatory responses. This scenario is likely one of the pathogenetic mechanisms that facilitate the transformation of simple steatosis into steatohepatitis when a fatty liver is exposed to second or third hits.
Ma
Xiong
X
Department of Gastroenterology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Disease, Shanghai, China.
Hua
Jing
J
Mohamood
Abdiaziz R
AR
Hamad
Abdel Rahmin A
AR
Ravi
Rajani
R
Li
Zhiping
Z
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology; D015704:CD4 Antigens / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects*; D005234:Fatty Liver / Q000188:drug therapy / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006505:Hepatitis / Q000188:drug therapy / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000502:physiology*
D000975:Antioxidants; D015704:CD4 Antigens; D004041:Dietary Fats; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D008070:Lipopolysaccharides; D019253:Proto-Oncogene Proteins c-bcl-2