In this respect, although this study did not show changes in IR or lipid profiles of 3-deazaneplanocin A mw rats exposed to CS, it is possible that longer exposures to CS may adversely affect these metabolic factors.23-26 Interestingly, the observation of increased hepatic injury induced by CS in the absence of worsening IR, together with the knowledge that CS also worsens IR23, 24 and IR in turn worsens NAFLD,21, 22 suggests that the deleterious effect of CS in human NAFLD and in CLD in general may engage several pathways. The 4-week study design may also have resulted

in an inability to demonstrate increased hepatic fibrosis. A second study limitation also is related to the assessment selleck of hepatic fibrosis. Although CS up-regulated the expression of genes involved in fibrogenesis in obese rats, this was not associated with evident development of increased liver fibrosis. However, the absence of a leptin receptor in the Zucker rat model may have influenced these results. Evidence for this possibility is that, although a methionine-choline–deficient diet induces steatohepatitis and increased oxidative stress in Zucker rats, the occurrence of increased neovascularization, hepatic expression of vascular endothelial growth factor, and liver

fibrosis development are restricted in this model.34 Therefore, although conclusions cannot be made regarding

the lack of increased angiogenesis and liver fibrosis development reported in the study by Azzalini et al., the CS-induced worsening of histological injury and apoptosis support the concept that CS may cause fibrosis progression in NASH.35 Additional studies in different animal models are needed to clarify and substantiate the profibrogenic effects of CS in NAFLD suggested by gene up-regulation. Finally, this study has demonstrated that CS increases hepatic PAK5 apoptosis in the livers of obese rats. This is of great importance given the crucial role of apoptosis in NAFLD progression. However, the exact apoptotic pathways involved were not identified. A key observation was that CS decreased caspase-3–driven apoptosis in both obese and control rats, and this suggests that CS induces a caspase-3–independent pathway in NAFLD. Further studies are warranted to elucidate the exact mechanism behind CS-induced apoptosis in NAFLD. In summary, the study by Azzalini et al.33 demonstrates that CS worsens liver injury in a rat model of obesity-related NAFLD. These results, together with other experimental data,25-29 provide compelling evidence that CS exacerbates NAFLD. Similarly, clinical studies in CLD have consistently indicated that CS aggravates liver injury in humans.8, 9, 11-17 There are very few published studies on the effects of CS in human NAFLD.