The Transcription Factor SREBP-1c Is Instrumental in the Development of औ-Cell Dysfunction

Abstract

We also found that the SREBP-1c processing in ␤-cells was irresponsive to acute stimulation of glucose and insulin, which was distinct from that in lipogenic tissues. However, 2-day exposure to these agents promoted SREBP-1c processing. Therefore, the SREBP-1c maturation could be implicated in the pathogenesis of ␤-cell glucolipotoxicity.

Visualising insulin secretion. The Minkowski Lecture 2004

“…We [93,94] and others [95,96] have recently shown that elevations of beta cell triglyceride content caused by overexpression of the lipogenic transcription factor sterol regulatory element binding protein (SREBP1c) leads to a substantial accumulation of intracellular lipid and the near-complete elimination of both phases of glucose-stimulated insulin secretion from beta cells and islets, consistent with reports of inhibitory effects on insulin secretion of lipid infusion in vivo [97] and the culture of islets with fatty acids in vitro [98]. The effects of SREBP1c overexpression are associated with decreased glucose-induced increases in cytosolic [ATP], vesicle motility at both low and high glucose concentrations, and a reduction in the number of glucose-stimulated release events [99] (Fig.…”

Chronic Activation of Liver X Receptor Induces β-Cell Apoptosis Through Hyperactivation of Lipogenesis

“…In ␤-cells, chronic highglucose treatment increases the nuclear form of ADD1/ SREBP1c, a process involving proteolytic cleavage and nuclear translocation (10,11). In addition, ectopic overexpression of mature ADD1/SREBP1c has been shown to increase intracellular lipid deposition and therefore to hinder glucose-stimulated insulin secretion (GSIS) and stimulate ␤-cell apoptosis (12,13).…”

Suppression of the Pancreatic Duodenal Homeodomain Transcription Factor-1 (Pdx-1) Promoter by Sterol Regulatory Element-binding Protein-1c (SREBP-1c)

“…The activation of SREBP-1c causes ␤ cell dysfunction, including impaired insulin expression and secretion in vitro (INS-1 cells) and in vivo (transgenic mice) (22,27). In both cases, reduction of PDX-1 was observed and was thought to contribute to ␤ cell dysfunction.…”

“…overexpression in ␤ cells caused impaired insulin secretion, suppression of insulin and pdx-1 expression, and reduction of ␤ cell mass (22,27). Next, we explored the effect of SREBP-1c on the Pdx-1 promoter.…”

“…Inhibition of insulin secretion by SREBP-1c is mediated through ATP consumption, UCP-2 and PDX-1 suppression, and granuphilin activation. Induced SREBP-1c expression in ␤ cells (INS-1) blunted nutrient-stimulated insulin secretion and decreased the mRNA of Pdx-1, insulin, and PDX-1 target genes (27). Conversely, in SREBP-1 knock-out mice, Pdx-1 mRNA expression increased (22).…”