Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Cell Mol Gastroenterol Hepatol. 2022;13(3):925-947. doi: 10.1016/j.jcmgh.2021.12.002. Epub 2021 Dec 8.
BACKGROUND & AIMS: Sphingosine 1-phosphate receptors (S1PRs) are a group of G-protein-coupled receptors that confer a broad range of functional effects in chronic inflammatory and metabolic diseases. S1PRs also may mediate the development of nonalcoholic steatohepatitis (NASH), but the specific subtypes involved and the mechanism of action are unclear.
We investigated which type of S1PR isoforms is activated in various murine models of NASH. The mechanism of action of S1PR4 was examined in hepatic macrophages isolated from high-fat, high-cholesterol diet (HFHCD)-fed mice. We developed a selective S1PR4 functional antagonist by screening the fingolimod (2-amino-2-[2-(4- n -octylphenyl)ethyl]-1,3- propanediol hydrochloride)-like sphingolipid-focused library.
The livers of various mouse models of NASH as well as hepatic macrophages showed high expression of S1pr4. Moreover, in a cohort of NASH patients, expression of S1PR4 was 6-fold higher than those of healthy controls. S1pr4 mice were protected from HFHCD-induced NASH and hepatic fibrosis without changes in steatosis. S1pr4 depletion in hepatic macrophages inhibited lipopolysaccharide-mediated Ca release and deactivated the Nod-like receptor pyrin domain-containning protein 3 (NLRP3) inflammasome. S1P increased the expression of S1pr4 in hepatic macrophages and activated NLRP3 inflammasome through inositol trisphosphate/inositol trisphosphate-receptor-dependent [Ca] signaling. To further clarify the biological function of S1PR4, we developed SLB736, a novel selective functional antagonist of SIPR4. Similar to S1pr4 mice, administration of SLB736 to HFHCD-fed mice prevented the development of NASH and hepatic fibrosis, but not steatosis, by deactivating the NLRP3 inflammasome.
S1PR4 may be a new therapeutic target for NASH that mediates the activation of NLRP3 inflammasome in hepatic macrophages.
鞘氨醇 1-磷酸受体（S1PRs）是一组 G 蛋白偶联受体，在慢性炎症和代谢性疾病中具有广泛的功能效应。S1PRs 也可能介导非酒精性脂肪性肝炎（NASH）的发展，但涉及的特定亚型和作用机制尚不清楚。
我们研究了各种 NASH 小鼠模型中哪种 S1PR 同工型被激活。我们在高脂肪、高胆固醇饮食（HFHCD）喂养的小鼠分离的肝巨噬细胞中研究了 S1PR4 的作用机制。我们通过筛选类似 fingolimod（2-氨基-2-[2-（4-正辛基苯基）乙基]-1,3-丙二醇盐酸盐）的鞘脂类聚焦文库，开发了一种选择性 S1PR4 功能拮抗剂。
各种 NASH 小鼠模型的肝脏以及肝巨噬细胞均显示 S1pr4 高表达。此外，在 NASH 患者队列中，S1PR4 的表达是健康对照组的 6 倍。S1pr4 敲除小鼠可防止 HFHCD 诱导的 NASH 和肝纤维化，而不改变脂肪变性。肝巨噬细胞中 S1pr4 的耗竭抑制了脂多糖介导的 Ca 释放，并使 Nod 样受体 pyrin 结构域包含蛋白 3（NLRP3）炎性小体失活。S1P 通过肌醇三磷酸/肌醇三磷酸受体依赖性[Ca]信号增加肝巨噬细胞中 S1pr4 的表达，并激活 NLRP3 炎性小体。为了进一步阐明 S1PR4 的生物学功能，我们开发了一种新型的 S1PR4 选择性功能拮抗剂 SLB736。与 S1pr4 敲除小鼠类似，SLB736 给药可通过使 NLRP3 炎性小体失活来预防 HFHCD 喂养小鼠 NASH 和肝纤维化的发生，但不能预防脂肪变性。
S1PR4 可能是 NASH 的一个新的治疗靶点，它介导肝巨噬细胞中 NLRP3 炎性小体的激活。
