| CREB-H belongs to the bZIP transmembrane transcription factor family that activates transcription by binding to cAMP responsive elements. CREB-H interacts with ATF-6 and binds to conserved elements in the APR genes to synergistically activate transcription. Evidence suggests that CREB-H is activated by cleavage upon ER stress, inflammatory stimuli, and metabolic stress (5,6). Known chemical activators of ER stress, such as tunicamycin and thapsigargin, have been shown to induce cleavage of the full-length 75 kDa from of CREB-H, releasing the 50 kDa N-terminal fragment, which translocates to the nucleus. Upon ER stress, the transmembrane domain of CREB-H is cleaved by Golgi proteases, which allows subsequent translocation to the nucleus. Liberated nuclear CREB-H plays a crucial role in the acute systemic inflammatory response by activating transcription of genes that encode serum amyloid P-component (SAP) and C-reactive protein (CRP). Recent studies suggest that activated CREB-H functions as a crucial metabolic regulator of hepatic lipogenesis, fatty acid (FA) oxidation, and lipolysis. Metabolic stress inducers, such as saturated fatty acids, insulin, and atherogenic high-fat diets have been shown to activate CREB-H in the liver. |
