Glucagon Receptor Deficiency Causes Early-Onset Hepatic Steatosis.

Summary

A consanguineous family harbored homozygous GCGR missense variants causing near-complete receptor loss-of-function, elevated glucagon and amino acids, adiposity, and hepatic steatosis. CRISPR-engineered iPSC hepatocytes carrying the same variants showed increased lipid accumulation, mechanistically linking impaired glucagon signaling to human steatosis and informing risk–benefit considerations for GCGR antagonists and agonists.

Key Findings

• Two rare homozygous missense GCGR variants cosegregated with early-onset hepatic steatosis/cirrhosis in a consanguineous family.
• Double GCGR mutations reduced membrane expression and signaling in cells, causing near-complete loss-of-function with elevated circulating glucagon and amino acids and increased adiposity.
• CRISPR/Cas9 introduction of the same variants into human iPSC-derived hepatocytes increased lipid accumulation, mechanistically linking GCGR loss to steatosis.
• Findings explain increased liver fat in GCGR antagonist trials and reduced liver fat with GCGR agonists.

Clinical Implications

Genetic or pharmacologic GCGR inhibition may promote hepatic steatosis; clinicians and developers should monitor liver fat with GCGR antagonists, while GCGR agonists may benefit patients with obesity and steatotic liver disease.

Limitations

• Single-family study limits generalizability and effect size estimation.
• Lack of longitudinal clinical outcomes beyond steatosis/cirrhosis and adiposity.

Future Directions

Expand to larger cohorts to assess variant spectrum and penetrance; evaluate liver outcomes in patients receiving GCGR antagonists/agonists; explore therapeutic modulation of amino acid metabolism.