Abstract
Carbohydrate response element binding protein (ChREBP) is an important transcription factor that regulates a variety of glucose-responsive genes in hepatocytes. To date, only two natural isoforms, Chrebpα and Chrebpβ, have been identified. Although ChREBP is known to be expressed in pancreatic β cells, most of the glucose-responsive genes have never been verified as ChREBP targets in this organ. We aimed to explore the impact of ChREBP expression on regulating genes linked to accumulation of lipid droplets, a typical feature of β-cell glucotoxicity. We assessed gene expression in 832/13 cells overexpressing constitutively active ChREBP (caChREBP), truncated ChREBP with nearly identical amino acid sequence to Chrebpβ, or dominant negative ChREBP (dnChREBP). Among multiple ChREBP-controlled genes, ChREBP was sufficient and necessary for regulation of Eno1, Pklr, Mdh1, Me1, Pdha1, Acly, Acaca, Fasn, Elovl6, Gpd1, Cpt1a, Rgs16, Mid1ip1,Txnip, and Chrebpβ. Expression of Chrebpα and Srebp1c were not changed by caChREBP or dnChREBP. We identified functional ChREBP binding sequences that were located on the promoters of Chrebpβ and Rgs16. We also showed that Rgs16 overexpression lead to increased considerable amounts of lipids in 832/13 cells. This phenotype was accompanied by reduction of Cpt1a expression and slight induction of Fasn and Pklr gene in these cells. In summary, we conclude that Chrebpβ modulates its own expression, not that of Chrebpα; it also regulates the expression of several metabolic genes in β-cells without affecting SREBP-1c dependent regulation. We also demonstrate that Rgs16 is one of the ChREBP-controlled genes that potentiate accumulation of lipid droplets in β-cells.
Highlights
Expression of glycolytic and lipogenic genes, including L-type pyruvate kinase (Pklr), acetylCoA carboxylase alpha (Acaca), thyroid hormone responsive (Thrsp) and fatty acid synthase (Fasn), is known to be regulated by glucose [1,2,3,4,5]
We evaluated the expression of other lipogenic genes, including regulator of G-protein signaling 16 (Rgs16), MID1 interacting protein 1 (Mid1ip1), and thioredoxin-interacting protein (Txnip) [37,38,39], and found that these genes were induced in caChREBP cells (Fig 2C) and were reduced in dnChREBP cells (Fig 2D)
We have shown that accumulation of lipid droplets, a major phenotypic characteristic in glucotoxic β-cells, appears to be mediated by Carbohydrate response element binding protein (ChREBP) expression, the mechanisms underlying this phenomenon are only partly understood
Summary
Expression of glycolytic and lipogenic genes, including L-type pyruvate kinase (Pklr), acetylCoA carboxylase alpha (Acaca), thyroid hormone responsive (Thrsp) and fatty acid synthase (Fasn), is known to be regulated by glucose [1,2,3,4,5]. PLOS ONE | DOI:10.1371/journal.pone.0147411 January 25, 2016
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