Regulation of the Expression of Lipogenic Enzyme Genes by Carbohydrate

Abstract

Diets high in simple carbohydrates and low in fats lead in the mammalian liver to induction of a set of enzymes involved in lipogenesis. This induction occurs, in part, through transcriptional mechanisms that lead to elevated levels of the mRNA for these enzymes. For most of the lipogenic enzymes, an increase in glucose metabolism is required to trigger the transcriptional response. The intracellular mediator of this signaling pathway is unknown, although evidence suggests either glucose-6-phosphate or xylulose-5-phosphate. Studies to map the regulatory sequences of lipogenic enzyme genes involved in the transcriptional response have been performed for the L-type pyruvate kinase, S14, and acetyl-coenzyme A carboxylase genes. These studies have identified the DNA sequences necessary to link the signal generated by carbohydrate metabolism to specific nuclear transcription factors.

Role of glucose-6-phosphate and xylulose-5-phosphate in the regulation of glucose-stimulated gene expression in the pancreatic β cell line, INS-1E

“…Cells were transfected with or without 100 pmols of siRNA targeting ChREBP or with the scrambled siRNA and 4 μL of Lipofectamine 2000 (Invitrogen). After 24 h of incubation in the medium containing 25 mM glucose or 25 mM 2DG, the cells studies: (1) HepG2 cells used in these studies have much lower glucokinase activity than normal hepatocytes [17,18], (2) in HepG2 cells, the glucose-induced gene expression between 5 and 25 mM glucose was not observed [19][20][21], and (3) although NADPH overproduction couples with lipogenesis, lipogenesis was not increased in liver infected by adenovirus bearing G6pdh cDNA [15]. Thus, to understand the regulation of ChREBP transactivity by glucose and its metabolites, it is important to elucidate whether G6P or X5P is the glucose signaling metabolite for ChREBP transactivation [21,22].…”

“…3A and 3B). ChoRE was identified by Towle et al [21], and is composed of two tandem E boxes spaced by 5 bp [28]. Glucose activates ChREBPα transactivity [27,29].…”

Regulation of gene expression by glucose

“…It consists of two E-box (or E-box like) sequences (5′-CAnnTG-3′) separated by five nucleotides (Towle et al 1997). The glucose response element of the FAS gene has not yet been identified, although experiments in transgenic mice suggest that the −2 kb region of the FAS promoter is sufficient to confer the ability to be regulated by nutrients (Girard et al 1997).…”

“…These different structures are involved in the binding to DNA and in protein-protein interactions. Among the transcription factors belonging to this class of proteins, USF/MLTF (for upstream stimulatory factor (major late transcription factor), designated USF) has been implicated as the mediator of glucose action (Vaulont & Kahn, 1994;Towle et al 1997). The tissue distribution of this factor is ubiquitous and does not seem to be altered by the nutritional or hormonal status.…”

The subcellular localization of the ChoRE-binding protein, encoded by the Williams–Beuren syndrome critical region gene 14, is regulated by 14-3-3

“…Elevated glucose levels in the liver lead to either gene transcriptional induction or post-translational activation of several key enzymes of glycolysis and lipogenesis, including fatty acid synthase, acetylCoA carboxylase and L-type pyruvate kinase (LPK) (1)(2)(3). The carbohydrate responsive element binding protein (ChREBP) transcription factor, the rat ortholog of Williams-Beuren syndrome critical region gene 14 [hereafter named WBSCR14 following recommendation of the HUGO Gene Nomenclature Committee (4)] is expressed under high-glucose diet and inhibited under high-fat diet in primary cultured hepatocytes.…”