Glucagon Receptor Deficiency Causes Early-Onset Hepatic Steatosis.

ABSTRACT: In mice, glucagon regulates lipid metabolism by activating receptors in the liver; however, its role in human lipid metabolism is incompletely understood. Here we describe three normal-weight individuals from a consanguineous family with early-onset hepatic steatosis and/or cirrhosis. Using exome sequencing, we found they were homozygous for two missense variants in the glucagon receptor gene (GCGR). In cells, the double GCGR mutation reduced cell membrane expression and signaling, resulting in an almost complete loss of function. Carriers of pathogenic GCGR mutations had substantially elevated circulating glucagon and amino acid levels and increased adiposity. Introducing the double GCGR mutation into human induced pluripotent stem cell-derived hepatocytes using CRISPR/Cas9 caused increas

SUBMITTER: Cacciottolo TM 

PROVIDER: S-EPMC12451087 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature