| The steroid sulfatase (STS)-mediated desulfation is a critical metabolic mechanism that regulates the chemical and functional homeostasis of endogenous and exogenous molecules. In this study, I first showed that the hepatic expression of STS was induced in the high-fat diet (HFD) and ob/ob models of obesity and type 2 diabetes. Over-expression of STS in the liver of transgenic mice alleviated HFD and ob/ob models of obesity and type 2 diabetes, including reduced body weight, improved insulin sensitivity, and decreased hepatic steatosis and inflammation. Interestingly, STS exerted its metabolic benefit through sex-specific mechanisms. In female mice, STS may have increased hepatic estrogen activity and consequently improved the metabolic functions; whereas ovariectomy abolished this protective effect. In contrast, the metabolic benefit of STS in males may have been accounted for by the male-specific decrease of inflammation in white adipose tissue (WAT) and skeletal muscle, as well as a pattern of skeletal muscle gene expression that favors energy expenditure.;Chronic inflammatory liver diseases are associated with estrogen excess and feminization in men. The estrogen excess was reasoned to be due to liver damage that weakens the liver's ability to breakdown estrogen. In this study, I showed that STS may have mediated the inflammation induced estrogen increase in chronic liver disease. Bioinformatic and IHC analysis demonstrated that STS was induced in liver samples from patients with chronic inflammatory liver diseases. In contrast, several enzymes involved in estrogen inactivation were down-regulated in diseased livers, including the phase I enzymes CYP1A2 and CYP3A4 and the phase II enzyme estrogen sulfotransferase (EST). Mechanistically, I showed that STS is an NF-kappaB target gene, whose induction facilitates the conversion of inactive estrogen sulfates to estrogens. On the other hand, loss of STS or blocking estrogen signaling increased NF-kappaB transcriptional activity and inflammation. These elucidated the activation of negative feedback loop, that is, STS induced by NF-kappaB in hepatocytes enhanced estrogen activity, which in turn suppresses NF-kappaB-mediated inflammation.;In summary, I have uncovered novel roles and mechanisms of STS in energy homeostasis and inflammation, which may facilitate the development of novel interventions for metabolic syndrome and chronic inflammatory liver disease. |
