INHBE

INHBE encodes activin βE, a liver-expressed secreted member of the TGF-β/activin family that functions as a hepatokine regulating both adipose fat storage and hepatocyte proliferation. In human genetics studies, heterozygous protein-truncating variants in INHBE—which reduce secreted activin E protein by ~90%—associate with favorable fat distribution (lower waist-to-hip ratio) and ~28% reduced odds of type 2 diabetes, and convergent loss-of-function associations in the receptor gene ACVR1C confirm that the activin E–ACVR1C signaling axis governs abdominal adiposity (PMID:35999217, PMID:35896531). Overexpression of activin βE in mouse liver inhibits regenerative DNA synthesis in hepatocytes, and activin βE is downregulated in rat and human liver tumors, indicating an additional growth-suppressive role in liver tissue homeostasis (PMID:12865331, PMID:16935389).

1. 2003 Medium

   Whether activin βE has any biological activity was unknown; liver-directed overexpression demonstrated that it inhibits hepatocyte DNA synthesis during regeneration, establishing activin E as a growth-inhibitory factor in the liver.

   Evidence In vivo nonviral hydrodynamic gene transfer to mouse liver with measurement of DNA synthesis during liver regeneration

   PMID:12865331

   Open questions at the time

   • Single gain-of-function approach without genetic loss-of-function confirmation in vivo
   • Whether endogenous activin E levels are sufficient to regulate liver regeneration was not tested
   • Receptor and downstream signaling pathway mediating the growth-inhibitory effect were not identified
2. 2006 Medium

   The relevance of activin βE to liver pathology was unclear; demonstration that INHBE is expressed in hepatocytes and downregulated in liver tumors positioned activin E within the growth-suppressive activin/follistatin axis in hepatocarcinogenesis.

   Evidence Real-time PCR and immunohistochemistry in chemically induced rat liver tumors and human liver tumors; DNA synthesis assays with follistatin and activin A

   PMID:16935389

   Open questions at the time

   • Growth-suppressive effects were demonstrated with activin A, not activin E directly, so the specific contribution of activin E to tumor suppression remains inferred
   • No genetic manipulation of INHBE in tumor models
   • Mechanism of INHBE downregulation in tumors was not elucidated
3. 2022 High

   Whether activin E has systemic metabolic functions was unknown; large-scale human exome studies revealed that INHBE loss-of-function variants confer favorable fat distribution and protection from type 2 diabetes, and concordant findings in the receptor gene ACVR1C established an activin E–ACVR1C signaling axis governing abdominal adiposity.

   Evidence Exome sequencing in >600,000 individuals across multiple cohorts with replication; in vitro characterization showing ~90% reduction in secreted protein for the most common pLOF variant

   PMID:35896531 PMID:35999217

   Open questions at the time

   • Direct demonstration of activin E signaling through ACVR1C at the biochemical level has not been shown
   • Mechanism by which reduced circulating activin E alters adipose tissue biology is unknown
   • No animal loss-of-function model has confirmed the metabolic phenotype

• Key open questions include the precise receptor complex engaged by activin E homodimers or heterodimers, the intracellular signaling cascade (Smad versus non-Smad) in adipocytes, and whether the liver growth-suppressive and metabolic roles are mediated through the same or distinct pathways.
• No crystal structure or binding affinity data for activin E with type I/II receptors
• No conditional knockout or knockdown model in liver or adipose tissue
• Whether activin E acts as homodimer or heterodimer with other β subunits in vivo is unresolved