The alleviating effect of sphingosine kinases 2 inhibitor K145 on nonalcoholic fatty liver

Biochem Biophys Res Commun. 2021 Nov 26:580:1-6. doi: 10.1016/j.bbrc.2021.09.060. Epub 2021 Sep 28.


Sphingosine kinase 2 (SphK2) inhibitors are developed for tumor therapy as considering its anti-tumor effect. Many studies also explored SphK2 modulated glucose and lipid homeostasis, which extended its potential function for metabolic diseases therapy. In this study, we discovered a significant reduction of hepatic lipid accumulation as well as recovery of liver function in ob/ob mice with intraperitoneal injection of K145. Also, db/db mice received K145 showed improvement of both NALFD and hyperglycemia. We furtherly analyzed the genes associated with lipid metabolism and found a remarkable decreased expression of lipogenic genes including FAS, ACC1 and SREBP1c whereas elevated mitochondrial fatty acid β-oxidation (FAO) related genes expression including CPT1A, MCAD, LCAD, PPAR-α, UCP2. Consistent to in vivo study, in vitro study also confirmed the role of K145 in decreasing lipid accumulation in human HL7702 cells, while inhibiting FAS, ACC1 and SREBP1c mRNA expression. It indicated a possible mechanism of K145 induced improvement of hepatic lipid accumulation partly via inhibition of lipigenesis. Our study suggested a promising role of K145 in drug development for NAFLD and diabetes therapy.

Keywords: Fatty acid oxidation; Hepatic lipid accumulation; K145; Lipogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Humans
  • Lipid Metabolism / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / drug therapy*
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Protein Kinase Inhibitors / therapeutic use*
  • Thiazolidinediones / therapeutic use*


  • 3-(2-aminoethyl)-5-(3-(4-butoxylphenyl)propylidene)thiazolidine-2,4-dione
  • Protein Kinase Inhibitors
  • Thiazolidinediones
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase 2, mouse
  • sphingosine kinase 2, human