Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences, Okazaki 444-8787, Japan.
Int J Mol Sci. 2023 Feb 14;24(4):3800. 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 (P2YR) 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 P2YR 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 P2YR 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 P2YR 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 P2YR knockout (KO) mice, while the disease marker levels such as serum AST and liver CCL2 mRNA in CDAHFD-treated P2YR KO mice were rather aggravated compared with those of CDAHFD-treated WT mice. Thus, P2YR may not contribute to the progression of liver injury, despite increased expression in NASH liver.
非酒精性脂肪性肝炎（NASH）是一种从非酒精性脂肪肝（NAFL）进展而来的疾病，其特征为炎症和纤维化。嘌呤能 P2Y 受体（P2YR）是一种促炎 G/G 家族蛋白偶联受体，据报道其参与肠道炎症和心血管纤维化，但它在肝发病机制中的作用尚不清楚。人类基因组学数据分析显示，从 NAFL 进展为 NASH 时，肝 P2YR mRNA 表达水平增加，与 C-C 基序趋化因子 2（CCL2）和胶原 Iα1 链（Col1a1）mRNA 的诱导呈正相关。因此，我们在 NASH 模型的小鼠中检查了 P2YR 功能缺失的影响，该模型使用胆碱缺乏、L-氨基酸定义的高脂肪饮食（CDAHFD）。用 CDAHFD 喂养 6 周可显著增加小鼠肝中 P2YR 的表达水平，与 CCL2 mRNA 的诱导呈正相关。出乎意料的是，CDAHFD 处理 6 周后，WT 和 P2YR 敲除（KO）小鼠的肝脏重量均增加，且伴有严重的脂肪变性，而 CDAHFD 处理的 P2YR KO 小鼠的血清 AST 和肝 CCL2 mRNA 等疾病标志物水平比 CDAHFD 处理的 WT 小鼠更为严重。因此，尽管 NASH 肝中 P2YR 的表达增加，但 P2YR 可能不会促进肝损伤的进展。
