CREB regulates the expression of neuronal glucose transporter 3: a possible mechanism related to impaired brain glucose uptake in Alzheimer’s disease

Impaired brain glucose uptake and metabolism precede the appearance of clinical symptoms in Alzheimer disease (AD). Neuronal glucose transporter 3 (GLUT3) is decreased in AD brain and correlates with tau pathology. However, what leads to the decreased GLUT3 is yet unknown. In this study, we found that the promoter of human GLUT3 contains three potential cAMP response element (CRE)-like elements, CRE1, CRE2 and CRE3. Overexpression of CRE-binding protein (CREB) or activation of cAMP-dependent protein kinase significantly increased GLUT3 expression. CREB bound to the CREs and promoted luciferase expression driven by human GLUT3-promoter. Among the CREs, CRE2 and CRE3 were required for the promotion of GLUT3 expression. Full-length CREB was decreased and truncation of CREB was increased in AD brain. This truncation was correlated with calpain I activation in human brain. Further study demonstrated that calpain I proteolysed CREB at Gln₂₈–Ala₂₉ and generated a 41-kDa truncated CREB, which had less activity to promote GLUT3 expression. Importantly, human brain GLUT3 was correlated with full-length CREB positively and with activation of calpain I negatively. These findings suggest that overactivation of calpain I caused by calcium overload proteolyses CREB, resulting in a reduction of GLUT3 expression and consequently impairing glucose uptake and metabolism in AD brain.     

n-Alkane and clofibrate, a peroxisome proliferator, activate transcription of ALK2 gene encoding cytochrome P450alk2 through distinct cis-acting promoter elements in Candida maltosa

The ALK2 gene, encoding one of the n-alkane-hydroxylating cytochromes P450 in Candida maltosa, is induced by n-alkanes and a peroxisome proliferator, clofibrate. Deletion analysis of this gene's promoter revealed two cis-acting elements-an n-alkane-responsive element (ARE2) and a clofibrate-responsive element (CRE2)-that partly overlap in sequence but have distinct functions. ARE2-mediated activation responded to n-alkanes but not to clofibrate and was repressed by glucose. CRE2-mediated activation responded to polyunsaturated fatty acids and steroid hormones as well as to peroxisome proliferators but not to n-alkanes, and it was not repressed by glucose. Both elements mediated activation by oleic acid. Mutational analysis demonstrated that three CCG sequences in CRE2 were critical to the activation by clofibrate as well as to the in vitro binding of a specific protein to this element. These findings suggest that ALK2 is induced by peroxisome proliferators and steroid hormones through a specific CRE2-mediated regulatory mechanism.