Knockout of Purinergic P2Y 6 Receptor Fails to Improve Liver Injury and Inflammation in Non-Alcoholic Steatohepatitis

• Published in: International journal of molecular sciences 2023-02, Vol.24 (4)
• Main Authors: Nishiyama, Kazuhiro, Ariyoshi, Kohei, Nishimura, Akiyuki, Kato, Yuri, Mi, Xinya, Kurose, Hitoshi, Kim, Sang Geon, Nishida, Motohiro
• Format: Article
• Language: English
• Subjects: Animals; Diet, High-Fat - adverse effects; Disease Models, Animal; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Receptors, Purinergic P2 - genetics; Receptors, Purinergic P2 - metabolism; RNA, Messenger - metabolism
• ISSN: 1422-0067
• DOI: 10.3390/ijms24043800

Nonalcoholic steatohepatitis (NASH) is a disease that progresses from nonalcoholic fatty liver (NAFL) and which is characterized by inflammation and fibrosis. The purinergic P2Y receptor (P2Y R) is a pro-inflammatory G /G 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 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 α1 chain (Col1a1) mRNAs. Therefore, we examined the impact of P2Y 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 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 R knockout (KO) mice, while the disease marker levels such as serum AST and liver CCL2 mRNA in CDAHFD-treated P2Y R KO mice were rather aggravated compared with those of CDAHFD-treated WT mice. Thus, P2Y R may not contribute to the progression of liver injury, despite increased expression in NASH liver.