43 As shown in Fig. 4, hepatic expression of activated pSTAT1 was markedly higher in HFD-fed IL-10−/−IL-6−/− and IL-10−/−STAT3Hep−/− dKO mice compared with IL-10−/− mice, indicating that IL-6/STAT3 activation is responsible for inhibiting STAT1 activation. In conclusion, IL-10−/− mice displayed Everolimus datasheet greater liver inflammatory response but less steatosis after ETOH or HFD feeding compared with WT mice, and inflammation-associated IL-6/STAT3 activation contributes to the reduced steatosis in these mice. Interestingly, hepatic IL-6/STAT3 is also activated

in WT mice after ETOH or HFD feeding, but to a lesser extent compared with IL-10−/− mice (Figs. 1-3). This finding suggests that endogenous IL-10 plays an important role in inhibiting hepatic IL-6/STAT3 activation, which may account for the weak activation of this signaling pathway in the liver in WT mice during ETOH or HFD feeding. buy GSK1120212 It has been reported that hepatic levels of IL-10 were elevated in mice after an 8 weeks of HFD feeding;28

however, we did not observe hepatic IL-10 up-regulation in WT mice after 12 weeks of HFD or 4 weeks of ETOH feeding. In contrast, we observed marked up-regulation of hepatic IL-10 mRNA in mice fed with HFD for 1 year (unpublished data). Furthermore, it has been reported that hepatic expression of IL-10 mRNA is not up-regulated in obese individuals without fatty liver but markedly up-regulated in those with fatty liver, which is further increased in individuals with NASH.44 This suggests that hepatic IL-10 is elevated after long-term HFD consumption in patients and

in mice, which may play a compensatory role in preventing inflammation in fatty liver disease. The fact that IL-10−/− mice had greater liver inflammatory response but less steatosis suggests that inflammation, as reported previously, may not only promote the development of fatty liver by producing TNF-α and IL-1 but may also ameliorate the fatty liver by producing cytokines (such as IL-6) that activate STAT3. Therefore, the overall effect of inflammation on hepatic steatosis is determined by the balance between detrimental cytokines that promote steatosis and hepatoprotective cytokines that prevent steatosis. It is of keen interest to explore the effect of inflammation on steatosis in patients with ASH and NASH. Recently, this website Bertola et al.44 reported that the liver of obese patients without obvious steatosis (S0) was associated with elevation IL-6 but not TNF-α and IL-1β. It is plausible that such elevation of inflammation-associated IL-6 plays a compensatory role in preventing the development of steatosis in the early stage of nonalcoholic fatty liver in obese patients. The liver of obese patients with severe steatosis (S3) and NASH was associated with highest fold induction of IL-6, followed by TNF-α and IL-1β. It is probable that the steatosis in these patients is modulated negatively by IL-6 but positively by TNF-α and IL-1β.