Blocking sphingosine 1-phosphate receptor 2 accelerates hepatocellular carcinoma progression in a mouse model of NASH

Area of Science:

• Hepatology
• Molecular Biology
• Oncology

Background:

• The role of sphingosine 1-phosphate (S1P) and its receptors (S1PRs) in non-alcoholic steatohepatitis (NASH) remains largely undefined.
• Melanocortin-4 receptor (Mc4r) deficiency contributes to NASH pathogenesis.

Purpose of the Study:

• To investigate the role of S1P/S1PRs in a murine model of NASH characterized by Mc4r deficiency.
• To evaluate the effects of S1PR antagonists on liver pathology and hepatocarcinogenesis.

Main Methods:

• Utilized a Melanocortin-4 receptor (Mc4r)-knockout (KO) murine model fed a Western diet (WD).
• Administered FTY720 (S1PR1, 3, 4, 5 antagonist) and JTE-013 (S1PR2 antagonist).
• Performed mRNA expression analysis, histological assessment, lipidomic, and metabolomic profiling.

Main Results:

• Mc4r-KO mice on WD showed altered S1PR mRNA expression (decreased S1pr1, increased S1pr2 and S1pr3).
• Blocking S1PRs, particularly S1PR2 with JTE-013, exacerbated liver fibrosis.
• JTE-013 treatment led to elevated S-adenosyl-l-methionine, reduced glycine N-methyltransferase (GNMT), and increased diacylglycerol (DG) and triacylglycerol (TG) levels, promoting hepatocellular carcinoma (HCC) susceptibility.
• Phenotypes mimicked Gnmt-KO mice, suggesting S1PR2 blockade triggers aberrant methylation and hepatocarcinogenesis.

Conclusions:

• The sphingosine 1-phosphate (S1P)/sphingosine-1-phosphate receptor 2 (S1PR2) axis plays a protective role against hepatocellular carcinoma (HCC) in NASH.
• Blocking the S1P/S1PR2 pathway can lead to aberrant methylation, increased lipid accumulation, and promote hepatocarcinogenesis.
• Targeting the S1P/S1PR2 axis could be a potential strategy for HCC prevention in non-alcoholic steatohepatitis (NASH) patients.