Knockout of Purinergic P2Y₆ Receptor Fails to Improve Liver Injury and Inflammation in Non-Alcoholic Steatohepatitis

Nonalcoholic steatohepatitis (NASH) is a disease that progresses from nonalcoholic fatty liver (NAFL) and which is characterized by inflammation and fibrosis. The purinergic P2Y(6) receptor (P2Y(6)R) is a pro-inflammatory G(q)/G(12) family protein-coupled receptor and reportedly contributes to intestinal inflammation and cardiovascular fibrosis, but its role in liver pathogenesis is unknown. Human genomics data analysis revealed that the liver P2Y(6)R mRNA expression level is increased during the progression from NAFL to NASH, which positively correlates with inductions of C-C motif chemokine 2 (CCL2) and collagen type I alpha 1 chain (Col1a1) mRNAs. Therefore, we examined the impact of P2Y(6)R functional deficiency in mice crossed with a NASH model using a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Feeding CDAHFD for 6 weeks markedly increased P2Y(6)R expression level in mouse liver, which was positively correlated with CCL2 mRNA induction. Unexpectedly, the CDAHFD treatment for 6 weeks increased liver weights with severe steatosis in both wild-type (WT) and P2Y(6)R knockout (KO) mice, while the disease marker levels such as serum AST and liver CCL2 mRNA in CDAHFD-treated P2Y(6)R KO mice were rather aggravated compared with those of CDAHFD-treated WT mice. Thus, P2Y(6)R may not contribute to the progression of liver injury, despite increased expression in NASH liver.