Noncanonical function of sphingosine kinase 2 (SPHK2) sustains hepatic triglyceride homeostasis - PubMed
3 days ago
- #hepatic steatosis
- #ATGL
- #SPHK2
- SPHK2 plays a noncanonical role in sustaining hepatic triglyceride homeostasis, independent of its enzymatic activity.
- Hepatocyte SPHK2 is downregulated in steatotic livers from both patients and mice with MASLD.
- Knockout of SPHK2 in hepatocytes promotes diet-induced hepatic steatosis by inhibiting ATGL-mediated triglyceride hydrolysis.
- Overexpression of SPHK2 in hepatocytes attenuates high-fat diet-induced hepatic steatosis by stabilizing ATGL.
- SPHK2 binds to ATGL, inhibiting COP1-mediated ATGL ubiquitination.
- KLF10 is identified as a transcription repressor responsible for the downregulation of SPHK2 in hepatocytes.
- Overexpression of the non-catalytic function of SPHK2 prevents hepatic steatosis in diet-induced mice.
- The findings suggest SPHK2's therapeutic potential for MASLD by promoting triglyceride hydrolysis in an enzymatic-independent manner.