Role of type 4 sphingosine-1-phosphate receptor in genesis of non-alcoholic steatohepatitis

Abstract

NLRP3 inflammasome activation is important in the pathogenesis of non-alcoholic steatohepatitis (NASH). Here we show that genetic depletion of S1PR4 protected mice from NASH development. Genetic depletion of S1pr4 also protected the mice against hepatic inflammation and fibrosis. S1pr4 depletion in hepatic macrophages inhibited lipopolysaccharide-mediated Ca++ release and deactivated the NLR Family pyrin domain containing 3 (NLRP3) inflammasome. S1P increased the expression of S1pr4 in hepatic macrophages and activated NLRP3 inflammasome through phospholipase C/inositol triphosphate (IP3) /IP3 receptor-dependent [Ca++] signaling. Administration of a novel sphingolipid SLB736 prevents development of NASH in mice by inhibiting NLRP3 inflammasome in Kupffer cells. SLB736 acted as a selective functional antagonist of S1PR4, and did not induce lymphopenia. S1PR4 may become a new therapeutic target of NASH.