09). It should be kept in mind that changes in adipose tissue IR is only one aspect by which TZDs may improve histology in NASH, and that many other systemic/local mechanisms (associated with changes in adipose tissue IR) are likely to play a role. Although dysfunctional fat clearly predisposed to hepatic steatosis (Table CX-5461 1) and necroinflammation (Fig. 6), contrary to what was expected, there was no additional effect of worsening adipose tissue IR on the NAS (Fig. 6). This would be consistent with a low threshold for FFA to trigger lipotoxicity and steatohepatitis, but also that other factors determine the severity of NASH.11, 12, 33, 34 Once FFA triggers intracellular inflammatory pathways, it appears that steatohepatitis

would depend less on the magnitude of the FFA/lipotoxicity insult than on other local factors. In contrast, liver fibrosis did show a susceptibility to more severe adipose tissue IR. Because fibrosis is strongly associated with the activation of hepatic stellate cells (HSCs),35 it is possible that the susceptibility to lipotoxicity may be different for hepatocytes,

compared to HSCs. Studies in vitro indicate that HSCs are very sensitive to exposure to palmitate and other long-chain fatty acids.36, 37 This has two major clinical NVP-LDE225 mw implications. First, adipose tissue IR may be an overlooked aspect regarding future risk for cirrhosis. Though obesity is an established risk factor for NASH progression10-13, 38 and cirrhosis,39 no previous studies have directly investigated the role of adipose tissue IR in relation to the natural history of the Selleckchem Palbociclib disease. Second, it may offer a novel target for disease prevention. Adiponectin is important in the regulation of HSC function.40-42 Because plasma adiponectin is decreased in NASH,43 modulation of its levels by peroxisome proliferator-activated receptor gamma agonists44 or by newer, more potent pharmacological agents may reverse fibrogenesis in this population.

A practical aspect of the study is the possible value of a simple index of adipose tissue IR (Adipo-IRi) to establish more accurately the metabolic effect of obesity in patients with NAFLD. The Adipo-IRi is derived from the plasma FFA x insulin concentration, and both measurements are quite simple, widely available, and rather inexpensive. Traditionally, BMI has been used as an indicator of metabolic risk in NAFLD.45, 46 Given the known limitations of BMI measurements,46, 47 we believed that a direct measure of adiposity, such as whole body fat by DXA, would be a more precise, useful guide of metabolic risk. However, neither was particularly helpful to assess metabolic risk associated with obesity. The Adipo-IRi has been proven useful in studying IR in patients with T2DM4 and the response to pioglitazone in patients with NASH.8 Abnormal Adipo-IRi was consistent with an impaired suppression of plasma FFA by insulin (Table 1) and a low plasma adiponectin concentration, which are all indicative of severe adipose tissue dysregulation.