Sex hormone affects the severity of non-alcoholic steatohepatitis through the MyD88-dependent IL-6 signaling pathway

Abstract

Recent research has shown that the occurrence of gender disparity in liver cancer associated with sex differences in MyD88-dependent IL-6 production, but the role of this signaling pathway in sex differences of non-alcoholic steatohepatitis (NASH) remains unknown. To investigate the effects of sex hormone-specific intervention on pathology and progression of NASH, and on the inflammatory TLR-MyD88-IL-6 signaling pathway NASH was modeled in C57/BL6 mice by feeding a methionine and choline-deficient (MCD) diet for 4 weeks. Male mice were subjected to sex hormone-related interventions such as orchidectomy, and orchidectomy combined with administration of either testosterone propionate or estradiol benzoate. Next, the degree of nonalcoholic fatty liver disease activity score (NAS), serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and the expression level of MyD88 and IL-6, were compared between these groups. Males developed more serious inflammatory problems and had a higher NAS than the females. Sex-specific intervention in male mice by orchidectomy reduced NAS, ALT, and AST, and the expression level of MyD88 and IL-6. But administration of exogenous androgen had no influence on either NAS or the expression of ALT, AST, MyD88, and IL-6. On the other hand, exogenous estrogen could alleviate the pathological damage caused by NASH, as well as reduce NAS, ALT and AST, and the expression of MyD88 and IL-6. The result show different sex hormone-related interventions affected the severity of NASH, possibly by modulating the level of sex hormones and regulating the TLR-MyD88-IL-6 signaling pathway.

Gestational bisphenol-A exposure lowers the threshold for autoimmunity in a model of multiple sclerosis

“…S4). The levels that we recorded were similar to those previously published by others for male (testosterone) and female (estradiol) mice (22,23). Our results do not support obvious hormonal modifications as a mechanism by which gestational BPA increases EAE susceptibility in adult male mice.…”

Nonalcoholic Fatty Liver Disease: A Challenge from Mechanisms to Therapy

“…Splenic artery resistive index (index of organ damage) overlapped between patients with NASH and those with fatty livers, but showed a difference to controls, pointing out that NASH patients did not present increased liver injury (followed by fibrosis and eventual portal hypertension) compared to fatty liver patients [29]. With regards to IL-6, most interestingly, recent results showed that different sex hormone-related interventions affected the severity of NASH, likely by impacting on the level of sex hormones and modulating the Toll-Like Receptor-MyD88-IL-6 signalling pathway, clearly reinforcing the hypothesis that IL-6 plays a key role in worsening the simpler fatty liver disease [30]. Finally, in a large, multi-ethnic population with NAFLD, IL-6 was independently associated with the prevalence and severity of subclinical atherosclerosis [31].…”

MicroRNA-26a–interleukin (IL)-6–IL-17 axis regulates the development of non-alcoholic fatty liver disease in a murine model

“…Plasma IL-6 values were increased in NASH patients in a pilot study [31]. Recent studies indicated that IL-6 contributed to the development of NAFLD [32,33]. IL-6 has also been demonstrated to play a pivotal role in the dichotomous differentiation programmes of Th17.…”