ChREBP binding to fatty acid synthase and L-type pyruvate kinase genes is stimulated by glucose in pancreatic β-cells

Abstract

Pancreatic b-cell dysfunction is central to the pathogenesis of type 2 diabetes and may involve secretory failure through glucolipotoxity. The relative importance of the transcription factors carbohydrate-responsive element binding protein (ChREBP), sterol-responsive element binding protein-1c (SREBP-1c), and upstream stimulatory factor (USF) in the induction of lipogenic genes by glucose remains unclear. By confocal imaging, we show that ChREBP translocates to the nucleus in MIN6 b cells in response to glucose. Both ChREBP and SREBP-1c were required for the induction of the fatty acid synthase (FAS) promoter by glucose, and chromatin immunoprecipitation (ChIP) assay revealed that glucose induced the binding of both ChREBP and SREBP-1c to the FAS promoter without affecting USF2 binding. By contrast, ChIP assay revealed that high glucose prompted direct binding of ChREBP, but not SREBP-1c or USF2, to the liver-type pyruvate kinase (L-PK) promoter. This event was indispensable for the induction of the L-PK gene by glucose, as demonstrated by RNA silencing, single-cell promoter analysis, and quantitative real-

ChREBP Mediates Glucose Repression of Peroxisome Proliferator-activated Receptor α Expression in Pancreatic β-Cells

“…ChREBP has previously been shown to activate the expression of the lipogenic genes L-PK and FAS in pancreatic ␤-cells (22,24). In line with a recent study performed in INS(832/13) cells (41), we show here that the induction by glucose of another lipogenic gene, GPDH, is mediated by ChREBP in INS-1E cells.…”

“…This reduction in ChREBP expression severely blunts glucose-induced FAS and L-PK expression (Fig. 5, C and D) in line with data from a previous study performed in the mouse insulinoma cell line MIN6 (24). Similarly, glucose induction of GPDH expression is also drastically reduced (Fig.…”

Genetic variation in genes of the fatty acid synthesis pathway and breast cancer risk

“…Transcription of the FAS gene is controlled synergistically by the transcription factors ChREBP (carbohydrate response elementbinding protein) and SREBP-1 (sterol response elementbinding protein-1). ChREBP binds directly to the endogenous promoter of the FAS gene in a glucose-dependent but insulin-independent manner and is absolutely required for its induction by glucose [16]. Sterol-responsive element binding protein-1 (SREBP-1) is an important transcription factor responsible for lipid accumulation in pancreatic islets in response to high glucose and insulin, through stimulation of acetyl-CoA carboxylase-1 and FAS [17,18].…”

Roles of Ca2+ ions in the control of ChREBP nuclear translocation

“…Our earlier work, using clonal MIN6 pancreatic b-cells, has suggested a role for changes in intracellular free Ca 2C concentrations in the activation of ChREBP by glucose because the use of diazoxide, an opener of ATP-sensitive K C channels that prevents membrane depolarisation and subsequent Ca 2C entry, inhibited ChREBP binding on the L-PK promoter at high glucose (da Silva Xavier et al 2006). Indeed, the activation of Ca 2C influx following glucose stimulation is another specific feature of the pancreatic b-cell compared with the hepatocyte (Prentki & Matschinsky 1987, Sudo & Mariash 1996.…”

“…In addition to its lipogenic role in the liver, ChREBP is a critical regulator of lipogenic genes in the pancreatic b-cell and may play a role in the development of glucolipotoxicity and b-cell failure through lipid accumulation and apoptosis in pancreatic islets of Langerhans in response to high glucose (Wang & Wollheim 2002, da Silva Xavier et al 2006, Cha-Molstad et al 2009, Noordeen et al 2010, Boergesen et al 2011. Table 1 shows a list of significant ChREBP target genes.…”