Background:
Metabolic dysfunction-associated steatohepatitis (MASH), previously known as non-alcoholic steatohepatitis (NASH), is an important phase in the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) to end-stage liver diseases, posing an increasing threat to public health worldwide with limited treatment options. In our pilot study, we have identified a liver-selective G protein-coupled receptor (GPCR) closely associated with MASH in mice.
Research question:
Whether there are associations between genetic variants of GPCRs and MASH in humans.
Objectives:
1. To determine whether genetic variants of GPCRs are associated with metabolic dysfunction-associated steatohepatitis (MASH) susceptibility and severity in humans;
2. To characterize the functional impact of genetic variants of GPCRs on hepatic gene expression and their correlation with histological or imaging-based MASH severity.
Scientific rationale:
This proposal directly addresses the unmet need for therapeutic targets in MASH by bridging rodent genetics to human translational validation, while exploiting genetic variant-phenotype associations to unravel the role of GPCRs in disease.