Rab2A modulates liver fibroblast growth factor 21 (FGF21) expression and systemic metabolism via apolipoprotein B-CREBH signaling.

ABSTRACT: Fibroblast growth factor 21 (FGF21) is a hepatokine that regulates systemic metabolism. Here, we delineate a novel regulatory pathway for FGF21 orchestrated by the small GTPase Rab2A. Our previous findings demonstrated that liver-specific deficiency of Rab2A impairs very low-density lipoprotein lipidation and promotes apolipoprotein B (APOB) accumulation. We now show that accumulated APOB drives the cleavage and activation of cAMP-responsive element-binding protein H (CREBH), a key hepatic transcription factor for FGF21 expression. Mechanistically, hepatic Rab2A inhibition protected mice from high-fat diet-induced obesity and was associated with markedly elevated circulating FGF21, the phenotype largely rescued by adenovirus-mediated knockdown of either CREBH or APOB. Collectively, we defi

SUBMITTER: Chen ZY 

PROVIDER: S-EPMC12774766 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature