Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3) (CREBH)

Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3), commonly known as CREBH, is a membrane-tethered transcription factor primarily expressed in the liver and small intestine (UniProt Q8TEY5). It plays a pivotal role in maintaining metabolic homeostasis by regulating genes involved in triglyceride metabolism, fatty acid oxidation, and glucose production (PubMed: 25107537). Beyond metabolism, CREBH is a critical regulator of the host intestinal barrier, where it modulates the expression of tight junction proteins such as Claudin-1 and Occludin to maintain epithelial integrity (PubMed: 30104255). In response to endoplasmic reticulum (ER) stress or metabolic signals, CREBH undergoes regulated intramembrane proteolysis, allowing its active N-terminal domain to translocate to the nucleus and initiate gene transcription (PubMed: 21803770). Dysregulation of this CREBH-mediated regulation is linked to the pathogenesis of nonalcoholic fatty liver disease (NAFLD), hypertriglyceridemia, and inflammatory bowel diseases, and it is also targeted by viruses like Hepatitis C to disrupt cellular barriers (PubMed: 28807918). While direct pharmacological modulators are still in the discovery phase, CREBH activity is influenced by existing metabolic drugs like fibrates, making it a significant target for therapeutic intervention in metabolic and barrier-related disorders.

Other names

CREB3L3cAMP-responsive element-binding protein 3-like protein 3CREB-HTranscription factor CREB-H

Acts as a transcription factor that, upon activation by regulated intramembrane proteolysis (RIP) in the Golgi, translocates to the nucleus to bind to specific DNA response elements, inducing the expression of genes involved in tight junction formation and metabolic regulation.