In this issue of HEPATOLOGY, Kahraman et al.13 report that hepatic NK cells, expression of NK cell–associated cytotoxic mediators (such as tumor necrosis factor–related apoptosis-inducing ligand [TRAIL]), NKG2D, and MICA/B messenger RNAs in the liver are significantly elevated in nonalcoholic steatohepatitis (NASH) and, to a lesser extent, in nonalcoholic fatty liver (NAFL), when compared to normal healthy control livers. Immunohistochemical analyses reveal

that MICA/B proteins are detected from hepatocytes in patients with NASH and NAFL. Moreover, the expression of MICA/B messenger RNAs are positively correlated with NAS score and hepatocyte apoptosis in NASH. These findings suggest that the MICA/B protein levels are up-regulated in hepatocytes from patients with NASH through mechanisms that have yet to be identified. check details This is then followed by activation of hepatic NK cells that release TRAIL as a means of killing hepatocytes, and thereby inducing hepatocelluar damage in these patients. It is not clear whether NK cells only kill MICA/B-positive hepatocytes or if they also kill MICA/B-negative cells. This could be confirmed by performing double-staining to determine whether MICA/B protein and terminal deoxynucleotidyl transferase–mediated dUTP nick-end Epigenetic Reader Domain inhibitor labeling (TUNEL+) hepatocytes are colocalized. Whereas the molecular mechanism underlying up-regulation of hepatic MICA/B

in NASH and NAFL patients was not explored in the study by Kahraman et al.,13 it has been well documented that expression of NKG2D ligands are up-regulated through a variety of stimuli that have been collectively termed “cellular stress”, such as cellular transformation, viral infection, and/or DNA damage.2, 3 It is known that fat accumulation can generate oxidative stress-induced DNA damage in hepatocytes,14 which may contribute to the up-regulation of hepatic MICA/B Protein kinase N1 in patients with NASH and NAFL. Interestingly, Kahraman et al.13 also show that levels of MICA/B messenger RNAs correlate positively with stage of fibrosis, suggesting that MICA/B also contribute to the progression of liver fibrosis. However, recent studies using

murine models of liver fibrosis suggest that the NKG2D-ligand interaction triggers the killing of activated hepatic stellate cells (HSCs) by NK cells through a TRAIL-dependent mechanism, thereby inhibiting liver fibrosis.15, 16 Liver fibrosis is a common scarring response to virtually all forms of chronic liver injury and is characterized by HSC activation and accumulation of collagen in the liver. In normal healthy livers, HSCs are quiescent, storing large amounts of vitamin A (retinol). During liver injury or culturing on plastic dishes, HSCs become activated and differentiate into myofiboblast cells that produce collagen. Activated HSCs can also become senescent during chronic liver injury or after 9–15 passages in vitro.