A Protective Role for CD154 in Hepatic Steatosis in Mice

Inflammation and lipid metabolism pathways are linked, and deregulation of this interface may be critical in hepatic steatosis The importance of the dialog between inflammatory signaling pathways and the unfolded protein response (UPR) in metabolism has been underlined Herein, we studied the role of CD! 54, a key mediator of inflammation, in hepatic steatosis To this end, Balb/c mice, wild-type or deficient in CD154 (CD154KO), were fed a diet rich in olive oil In vitro, the effect of CD154 was studied on primary hepatocyte cultures and hepatocyte-derived cell lines Results showed that CD154KO mice fed a diet rich in olive oil developed hepatic steatosis associated with reduced apolipoprotein B100 (apoB100) expression and decreased secretion of very low-density lipoproteins This phenotype correlated with an altered UPR as assessed by reduced X-Box binding protein-1 (XBP1) messenger RNA (mRNA) splicing and reduced phosphorylation of eukaryotic initiation factor 2 alpha Altered UPR signaling in livers of CD154KO mice was confirmed in tunicamycin (TM) challenge experiments Treatment of primary hepatocyte cultures and hepatocyte-derived cell lines with soluble CD 154 increased XBP1 mRNA splicing in cells subjected to either oleic acid (OA) or TM treatment Moreover, CD 154 reduced the inhibition of apoB100 secretion by HepG2 cells grown in the presence of high concentrations of OA, an effect suppressed by XBP1 mRNA silencing and in HepG2 cells expressing a dominant negative form of inositol requiring ER-to-nucleus signaling protein-1 The control of the UPR by CD 154 may represent one of the mechanisms involved in the pathophysiology of hepatic steatosis Conclusion Our study identifies CD154 as a new mediator of hepatic steatosis (HEPATOLOGY 2010,52 1968-1979)