Thus, enhanced adiposity can either through the interaction between adipocytes

BMN 673 and immune cells, or the overloading of hepatocytes with fat, result in inflammation, IR, and steatosis. Transgenic strategies involving whole-body and tissue-specific gene modulation in elegant mouse models clearly illustrate the contribution of both adipocytes and hepatocytes. For example, genetic changes in adipocyte c-Jun NH2-terminal kinase (JNK1),9 or hepatocyte glycoprotein 130 (gp130)10 and IκB kinase-β11 can regulate IR and steatosis. However, in humans, adipocyte growth and liver steatosis occur over a protracted time frame. Thus, although the rodent studies are highly informative, it is likely that the combination of the two promotes IR and its consequences, including nonalcoholic fatty liver

disease increasingly seen BMS907351 by hepatologists. Fas (CD95), a member of the TNF family, is expressed by most tissues and plays an important role in mediating programmed cell death (apoptosis). The binding of Fas ligand (FasL) to Fas assists in the formation of the death-inducing signaling complex (DISC), leading to the activation of caspase-8 and caspase-3 and thereby apoptosis. However, as for TNF-α, evidence now suggests that Fas may be involved in nonapoptotic activities.12 For example, in terms of inflammation, Fas can promote the secretion of proinflammatory cyokines

such as IL-1α, IL-1β, IL-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1).13, 14 Moreover, anti-CD95 antibodies can cause massive apoptosis of hepatocytes in vivo,15 MCE公司 but these antibodies can accelerate regeneration in partially hepatectomized livers,16 suggesting additional nonapoptotic functions of Fas. In humans, Fas is expressed in preadipocytes, adipocytes,17 and hepatocytes12 and the Fas receptor has been shown to mediate apoptosis in both adipocytes and the liver. However, adipocyte apoptosis during obesity and in human adipocytes in culture under reduced serum conditions is limited. This may be explained by adipocyte-produced insulin growth factor-1 inhibiting FasL-induced adipocyte apoptosis.17 In order to examine the role of Fas in adipocyte function and in regulating inflammation, Wueest et al.18 recently undertook a detailed in vitro and in vivo study. They observed up-regulation of Fas expression in the perigonadal fat pads of db/db, ob/ob, and high-fat diet (HFD)-fed wild-type mice and in the fat tissues of obese patients, and observed further elevated Fas expression in obese patients with type 2 diabetes. Based on these preliminary observations and in order to analyze the role of increased Fas expression, the authors then utilized total-body Fas knockout (FasKO) mice and determined the effects of high-fat feeding.