INHBE

INHBE encodes activin E, a secreted hepatokine highly and specifically expressed in hepatocytes that functions as a liver-derived negative regulator of adipose storage (PMID:35999217). Large-scale human exome studies link rare predicted loss-of-function variants in INHBE to lower waist-to-hip ratio adjusted for BMI and reduced odds of type 2 diabetes, and in vitro the most common pLOF variant cuts secreted protein levels by roughly 90%, establishing that these variants act by impairing secretion (PMID:35999217). Parallel association of WHRadjBMI signals with variants in the activin receptor ACVR1C places activin E upstream of ACVR1C in a signaling axis controlling fat distribution (PMID:35896531). In the liver itself, the activin βE subunit is implicated in regulating hepatocyte proliferation, being upregulated early in liver regeneration models inversely with proliferation indices and down-regulated in liver tumors (PMID:15916968, PMID:16997617). Beyond this human-genetic pathway placement and correlative hepatic expression data, no direct biochemical reconstitution of the activin E–ACVR1C interaction has been characterized in the available corpus.

1. 2005 Low

   Whether the activin βE subunit has any regulated role in liver biology was unestablished; measuring its expression during regeneration tied it to hepatocyte proliferation control.

   Evidence RT-PCR of activin subunit mRNA with PCNA labeling in rat partial hepatectomy and portal vein ligation models

   PMID:15916968

   Open questions at the time

   • Correlative mRNA only, no direct functional manipulation of INHBE
   • Rat model; human relevance not addressed
   • No receptor or downstream mechanism defined
2. 2006 Low

   Building on regeneration data, the βE subunit was linked to growth inhibition in the liver and to dysregulation in liver tumors, suggesting a tumor-suppressive proliferation-restraining role.

   Evidence Expression analysis and functional summary in liver tumor models (review)

   PMID:16997617

   Open questions at the time

   • Review-level summary with limited methodological detail
   • Growth-inhibitory effect not mechanistically dissected for βE specifically
   • No secreted-protein or receptor data
3. 2022 Medium

   Whether INHBE has a systemic metabolic function in humans was unknown; large exome studies established it as a hepatokine whose loss-of-function protects against abdominal obesity and type 2 diabetes, and an in vitro secretion assay showed the common pLOF variant impairs protein secretion.

   Evidence Exome sequencing of 618,375 individuals with in vitro characterization of the in-frame deletion pLOF variant showing ~90% reduced secretion

   PMID:35999217

   Open questions at the time

   • Single-lab functional follow-up with one secretion assay
   • Mechanism of how reduced activin E lowers adipose storage not demonstrated biochemically
   • No in vivo demonstration of the metabolic effect
4. 2022 Medium

   To place activin E in a signaling pathway, parallel association of WHRadjBMI with ACVR1C variants implicated the activin type I receptor ACVR1C as the relevant receptor, indicating activin E signals through ACVR1C to regulate fat distribution.

   Evidence Exome sequencing of 362,679 individuals with independent replication and parallel ACVR1C genetic association

   PMID:35896531

   Open questions at the time

   • Pathway inferred from genetic co-association, not direct INHBE–ACVR1C binding
   • Downstream signaling effectors in adipose tissue not defined
   • Cell type mediating the receptor effect not identified

• Direct biochemical demonstration of activin E binding and activating ACVR1C, and the downstream signaling that links the hepatokine to adipose storage, remain unresolved.
• No reconstituted activin E–ACVR1C interaction
• Downstream signaling cascade in adipocytes uncharacterized
• Mechanistic basis for protection from type 2 diabetes not established