Major Histocompatibility Complex Class I-related Chains A and B (MIC A/B): A Role in the Pathogenesis of Non-alcoholic Steatohepatitis

Hepatocellular apoptosis is a key mechanism of liver injury in the pathogenesis of non-alcoholic steatohepatitis (NASH). Recently, soluble forms of major histocompatibility complex (MHC) class I-related chains A and B (MIC A/B) were reported to be increased in the sera of patients with chronic liver disease and hepatocellular malignancy. However, the role of MIC A and B in the pathogenesis of NASH has not been explored. We thus aimed to investigate the impact of these stress-induced ligands on liver injury, apoptosis and hepatic fibrosis in patients with NASH. Methodology: Blood and liver tissue were obtained from 40 patients with NASH undergoing gastric banding for obesity. The control group consisted of 10 healthy volunteers. Real-time PCR was used to measure mRNA transcripts of MIC A/B and the death receptors CD95/Fas, TRAIL-DR4 and DR5. Intrahepatic liver cell apoptosis was quantified by TUNEL assay, and on the systemic level, apoptosis was determined by the caspase-cleaved biomarker M30. Liver injury was assessed by histopathology using the NAFLD activity score (NAS) and serum ALT/AST determinations. Hepatic fibrosis was assessed by Sirius-Red staining, and mRNA transcript for α-SMA. Results: Our preliminary data from patients with NASH following gastric banding revealed significant increases (p<0.05) (i) in hepatic MIC A/B mRNA by >2.8; (ii) in CD95/Fas, DR4 and DR5 mRNAs; (iii) in TUNEL+ hepatocytes by >4.1; and (iv) in systemic M30 levels. Consistent with this data, histological examination of livers from NASH patients revealed relevantly increased NAS scores. Serum ALT and AST values were significantly higher in NASH patients. Hepatic fibrosis was >2.6 increased in patients with NASH. Conclusion: In patients with NASH, hepatocyte apoptosis and hepatic fibrosis are increased. Our findings suggest a role for MIC A/B-mediated liver injury. Thus, therapeutic intervention aimed at reducing MIC A/B may have a beneficial effect on the progression of NASH.

NASH - Stress - ligands