I read with interest an excellent study by Ma et al. that clarified the mechanisms of progression from hepatic steatosis to nonalcoholic steatohepatitis (NASH) in a mouse model of a high-diet-induced fatty liver.1 The authors revealed that CD4+ CD25+ forkhead box P3+ hepatic regulatory T cells (T regs) decreased during the administration of a high-fat diet, and the levels of T regs were less than half of those in control mice at the end of the 8-week experiment. Marked reduction of T regs, which was caused by apoptosis due to oxidative stress, was associated with enhanced expression of tumor necrosis factor (TNF) alpha and its intracellular mediators in liver. Adoptive-transferred T regs suppressed high-fat diet-induced intrahepatic TNF alpha signaling. Mice in which T regs were depleted or T regs were transferred, both of which were fed diets containing a high amount of fat, were given a single relatively low dose of lipopolysaccharide (LPS) (100 μg/mouse) to induce hepatic injury. Six hours after injection of LPS, LPS-induced liver damage was compared between the groups. A pretreatment with adoptive transfer of T regs significantly attenuated hepatotoxicity of LPS in mice with hepatic steatosis. The authors speculate that enhanced LPS signaling followed by proinflammatory cytokine production as a second hit necessary for the progression from steatosis to nonalcoholic steatohepatitis can be reduced by restoring the function of T regs.
T regs are engaged in the regulation of organ-specific immune responses to pathogens and self-proteins. A recent in vitro study indicates that activated T regs rapidly inhibit induction of Th1 cytokine mRNA, whereas suppression of anti-inflammatory Th2 cytokines is delayed.2 This article by Ma and colleagues may be the cornerstone for a better understanding of a variety of immune-related liver diseases in addition to nonalcoholic liver disease. I would like to ask the authors whether animal models with chronic endotoxemia, which are described in a recent article,3 are more suitable than those with acute endotoxemia for the study to investigate the role of T regs in liver disease. Mild chronic endotoxemia has been observed in chronic liver disease,4 chronic kidney disease,5 and chronic cardiovascular disease.6