Hepatic GPR110 contributes to sex disparity in the development of MASH through oestrogen receptor α-dependent signalling.
Summary
This study identifies GPR110 as a liver-selective GPCR that drives sex-specific susceptibility to MASH. Hepatocyte Gpr110 deletion protects females but not males, a human GPR110 variant correlates with higher MASLD prevalence in women, and the protective phenotype depends on hepatic ERα.
Key Findings
- Hepatocyte-specific Gpr110 knockout protected female but not male mice from MASH.
- Human GPR110 variant rs937057 T>C was associated with higher MASLD prevalence in women.
- Knockdown of hepatic ERα (Esr1) abolished the protective phenotype in female mice, indicating ERα dependence.
Clinical Implications
Suggests targeting GPR110 or modulating ERα-dependent hepatic signaling as sex-specific strategies for MASH. Supports risk stratification in women carrying GPR110 variants.
Why It Matters
Reveals a sex-specific GPCR–ERα axis in MASH pathogenesis, opening avenues for precision, female-targeted therapies. Integrating mouse genetics with human variant data strengthens translational potential.
Limitations
- Detailed downstream G-protein signaling mechanisms are not fully delineated in the abstract.
- Sample sizes and independent human replication cohorts are not specified.
Future Directions
Define the precise G-protein pathways downstream of GPR110 in hepatocytes, validate associations in diverse human cohorts, and develop/selective GPR110 modulators for sex-specific MASH intervention.
Study Information
- Study Type
- Case series
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic evidence using hepatocyte-specific knockout mice with supporting human genetic association.
- Study Design
- OTHER