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

## TL;DR

This study identifies a new pathway involving Rab2A, APOB, and CREBH that regulates FGF21, a liver hormone affecting metabolism and obesity.

## Contribution

The paper reveals a novel Rab2A–APOB–CREBH signaling axis that controls FGF21 expression and systemic metabolism.

## Key findings

- Rab2A inhibition in the liver increases FGF21 and protects against high-fat diet-induced obesity.
- Accumulated APOB activates CREBH, which is critical for FGF21 expression.
- Disrupting CREBH or APOB reduces the protective effects of Rab2A inhibition.

## 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 define a Rab2A–APOB–CREBH axis that is potentially essential for the hepatic regulation of FGF21.