Analysis of Abnormal Iron Metabolism and Efficacy of Iron Reduction Therapy in Patients With Nonalcoholic Steatohepatitis

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Background: Nonalcoholic fatty liver disease (NAFLD), which is the liver's manifection of metabolic syndrome, includes a wide spectrum of liver diseases, ranging from pure fatty liver to nonalcoholic steatohepatitis (NASH). A crucial event in the initiation of NASH seems to involve early lipid accumulation and lipid peroxidation in the hepatocytes, followed by kupffer cells (KC) and hepatic stellate cells activation. However, the mechanism of NASH progression is still unknown. Recently, because some study groups have reported that NASH patients have chronic stress, the association between stress and NASH progression has been suspected. Neuroendocrine mediators produced from hypothalamic pituitary adrenal axis, such as cortisol or norepinephrine (NE), have been known to affect immune cells. It is possible that KC affected by stress induced mediators are involved in the NADH initiation. In this study, we investigated the involvement of chronic stress on NASH progression with a murine restraint stress (RST) model. Methods: Five weeks old male C57/BL6j mice were used in this study. Mice were fed the methionine and choline deficient (MCD) diet or control diet for 8 weeks. RST was loaded on mice with placing in well-ventilated 50 ml conical tubes for 6 hrs twice a week. In some experiments, clodronate lyposomes were administrated in mice with injection to deplete KC. Mice were randomly divided into six groups : (1) MCD diet only (n=9), (2) MCD diet and RST (n=7), (3) MCD diet, RST and KC depletion (n=7), (4) control diet only (n=5), (5) control diet and RST (n=8), (6) control diet, RST and KC depletion (n=8). After 8 weeks, the degrees of steatohepatitis were histologically analyzed in all groups. Results: By loading RST, serum cortisol (1.27±0.29 vs. 1.97±0.35, p < 0.05) and hyaluronic acid (113.3±36.3 vs. 191.5±77.9, p < 0.05) were elevated, and liver steatosis was occurred in mice fed control diet. Next, the administration of MCD diet was induced steatohepatitis, and serum ALT, cortisol, hyaluronic acid (106±84, 2.3±0.3, 256.3±78.9 in MCD vs. 119±64, 2.5±0.5, 293.3±197.9 in MCD plus RST) and steatohepatitis induce by MCD diet were aggravated by loading RST. However, when mice were treated with clodronate lyposomes to deplete KC, the degree of liver steatosis and fibrosis were decreased in mice fed MCD diet or loaded RST. Conclusion: M2 macrophages, which are induced by cortisol or IL-10, have known to produce TGF-β. These results suggest that chronic stress may be involved in the progression of NASH through the alternative activation of KC. Reduction of mental or physical stress may be decreased the risk of NASH in NAFLD patients.