Star, which we have shown to be produced in beta cells, is responsible for transport of cholesterol into mitochondria for the production of steroids. We previously found that Star is upregulated with islet amyloid deposition and this is associated with mitochondrial dysfunction. In steroidogenic tissues, StAR transcription is acutely regulated by cAMP Regulatory Element Binding protein (CREB).
To determine whether upregulation of Star expression by islet amyloid deposition is regulated by CREB activation, we studied the effects of amyloid formation in human islet amyloid polypeptide (hIAPP) transgenic islets in vitro (16.7 mM glucose for 144 hrs) and in vivo (high fat diet; HFD for 6 months).
In vitro phosphorylation of CREB (pCREB) and Star expression increased only with amyloid formation (Table; Expt 1a), as did expression of other known CREB target genes (Expt 1b). When islets were cultured with the amyloid inhibitor Congo red (CR; 200 μM), the increase of CREB target genes was abrogated (Expt 2), suggesting chronic activation of CREB is downstream of amyloid deposition. Amyloid deposition in vivo was also associated with upregulation of Star and other CREB target genes (Expt 3).
In summary, chronic CREB activation is associated with increased Star expression, suggesting a novel pathway for amyloid-induced mitochondrial dysfunction in beta cells.
M.F. Hogan: None. N. Esser: None. A.T. Templin: None. J.J. Castillo: None. S. Zraika: Research Support; Self; Novartis Pharmaceuticals Corporation. R.L. Hull: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc.
American Diabetes Association (1-18-PDF-174 to M.F.H.); U.S. Department of Veterans Affairs (I01BX001060)
