The recruitment of TNF receptor–associated factor 2 (TRAF2) mediates the proinflammatory consequences of CD154/CD40 interaction.61, 62 As IRE1 recruits TRAF2 upon activation, TRAF2 may represent a potential link between the CD40 and IRE1 signalization pathways. Our study does not exclude other mechanisms through which CD154 may
interfere with the progression of liver steatosis. These may involve deregulation of the cytokine network. Indeed, CD154 induces inflammatory cytokines, some of which play a role in lipid metabolism, such as IL-6. IL-6 alleviates liver steatosis63 and IL-6−/− mice develop mature-onset obesity and are prone to hepatic steatosis and metabolic alterations.64, 65 According to the regulatory role of CD154 on IL-6 expression, we found that CD154KO PI3K Inhibitor Library purchase mice showed impaired induction of IL-6 following the olive oil–rich diet as shown by a reduced induction of plasma IL-6 levels and liver IL-6 mRNA (Supporting Fig. 9A,B). Hence, the down-regulation of IL-6 expression may provide another mechanism to explain the steatotic phenotype of olive oil–fed CD154KO mice. ER stress also leads to IL-6 production through XBP-1 signaling59, 66 and, accordingly, in HepG2 cells expressing a dominant negative form of IRE1, TM-induced expression of IL-6 was impaired. In this context, the CD154-dependent IL-6 induction selleck monoclonal humanized antibody inhibitor was preserved (Supporting Fig. 9A,B). Therefore, the control
of IL-6 expression is likely to represent another interface linking CD154, the UPR, and hepatic lipid metabolism. This observation suggests that several integrated signaling pathways are likely to account for the contribution of CD154 Urease in hepatic steatosis. In conclusion, our study shows that CD154 is a mediator involved in the natural history of hepatic steatosis. CD154 appears as a new link between lipid metabolism and inflammation in the liver, supporting the idea of interdependency between inflammation and metabolic disorders.27, 32 The authors thank Chantal Combe, Jérôme Gabet, Alexandra Nicou, and Antonio Palos Pinto for technical help. Additional Supporting Information may be found in the online version of this
“See article in J. Gastroenterol. Hepatol. 2012; 27: 789–796. Nonalcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH) is a progressive form of NAFLD with the potential for progression to cirrhosis. The pathogenesis of NASH is incompletely understood, but may involve hyperendotoxemia1 secondary to impaired phagocytotic function of Kupffer cells (KCs)2 and consequent KC overproduction of and increased sensitivity to cytokines such as tumor necrosis factor (TNF)-α and interleukin-1β (IL-1β).3 Impaired phagocytotic function of KCs may therefore lead to higher endotoxin levels in the systemic circulation, as has been observed in patients with NASH and in animal models of NASH.