It should be mentioned, however, that the role of CHOP

in human NASH as a driver of hepatocyte apoptosis is in dispute.80,84 Finally, despite a clear pathway of understanding in the development of hepatic IR, the discovery by Czaja and colleagues that the elimination of fat stores by lysosomal degradation pathway, or autophagy, may have profound implications for not just this website NAFLD but hepatic IR because the storage of FFA may be dangerous and also perpetuate hepatocyte IR.85 Furthermore, the process of rapid clean up of fats either by macroautophagy or chaperone-mediated autophagy promotes hepatocyte resistance to oxidative stress.86 Although limited here, for further review readers are encouraged to see the most recent

review on autophagy and the liver because data implicate the failure of hepatocyte autophagic function can lead to the development of a fatty liver.87 The issue of susceptibility of race or ethnicity to NAFLD progression was recently highlighted by the discovery of a point mutation in the gene encoding for adiponutrin, or PNPLA3, in which Hispanics were far more likely to have more hepatic fat and inflammation if they had an allelic variant. Conversely, non-Hispanics and African-Americans were more likely to have a protective allelic variant, and were less likely to have either excess hepatocyte fat or inflammation.88,89 It should be noted that the association between PNPLA3 polymorphisms and NAFLD is GDC0449 independent of IR. Studies have shown an association between fatty liver and altered glucose tolerance/diabetes alone or in the setting of MS.90–98 Such an association is found in cross-sectional90–96 and confirmed by prospective studies. Although limited by their

Reverse transcriptase study design, cross-sectional studies offer some interesting hints. For instance, they indicate that the pathogenesis of NAFLD could be sex-specific;90 that NAFLD patients display metabolic abnormalities indistinguishable from those observed in diabetic and obese patients;91 and that it is difficult to dissociate the development of T2D alone from the development of the MS on the grounds that NAFLD is a risk factor for both.94,95 Finally, NAFLD is associated with IR rather than with impaired β-cell viability,95,96 implying that the development of T2D will not occur other than in the presence of a genetic predisposition. Prospective studies provide the most robust evidence, given that they are based on both surrogate indices, hepatobiliary enzymes97–104 and on the natural history of NAFLD.105–108 It should be acknowledged that liver enzymes are insensitive and non-specific for the diagnosis of NAFLD. Moreover, imaging studies have been performed in Asian populations alone. A recent meta-analytical study quantified that NAFLD has a twofold risk of T2D.5 Knowledge of subsets of NAFLD patients particularly prone to developing T2D is critical in envisaging strategies of prevention.