A protective role for CD154 in hepatic steatosis in mice

Abstract

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 CD154, 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 2a. 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 CD154 increased XBP1 mRNA splicing in cells subjected to either oleic acid (OA) or TM treatment. Moreover, CD154 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 CD154 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

CD40L Deficiency Ameliorates Adipose Tissue Inflammation and Metabolic Manifestations of Obesity in Mice

“…35,36 We found that in CD40L Ϫ/Ϫ mice, liver steatosis and NASH were strongly reduced, as were the expression levels of genes involved in glycolysis, fatty acid synthesis, and fat uptake. Contrary to our results, Villeneuve et al 37 found that CD40L was protective against the development of steatosis after administration of olive oil. However, the different dietary stresses that are used in the 2 models may be accountable for this difference.…”

CD40 deficiency in mice exacerbates obesity-induced adipose tissue inflammation, hepatic steatosis, and insulin resistance

“…CD40 Ϫ/Ϫ mice develop hepatic steatosis and increased de novo lipogenesis in the liver. Recent literature has implicated CD40L as a protective factor against hepatic steatosis (43,46), which has a strong association with insulin resistance (29). Since we found impaired systemic insulin sensitivity in CD40…”

“…In fact, the CD40-CD40L axis has recently been implicated in the pathogenic complications of obesity (32,43,46). However, various research groups have reported conflicting roles of CD40L in diet-induced obesity in mice.…”

“…However, various research groups have reported conflicting roles of CD40L in diet-induced obesity in mice. For example, two studies showed that CD40L deficiency aggravated hepatic steatosis in obesity (43,46) whereas an-other study indicated that the absence of CD40L attenuated diet-induced steatosis (32). Furthermore, in one study, CD40L deficiency improved insulin resistance (32), whereas in another study lack of CD40L in mice did not ameliorate high-fat diet-induced insulin resistance (46).…”

Naltrexone attenuates endoplasmic reticulum stress induced hepatic injury in mice

“…Tunicamycin (TM), a bacterial nucleoside antibiotic, can induce pharmacologic ER stress and stimulate unfolded and misfolded protein accumulation in ER. Numerous documents demonstrated that TM challenge could increase gene expression of GRP78 and Chop, as ER stress markers (10,36). Other studies also revealed that ER stress induction by hemocystein and TM led to hepatic steatosis in in vitro and in vivo models (24,36).…”