Abstract:The transcription factor carbohydrate response element‐binding protein (ChREBP) is a member of the basic helix‐loop‐helix leucine zipper transcription factor family. Under high‐glucose conditions, it has a role in regulating the expression of key genes involved in various pathways, including glycolysis, gluconeogenesis and lipogenesis. It does this by forming a tetrameric complex made up of two ChREBP/Mlx heterodimers, which enables it to bind to the carbohydrate response element (ChoRE) in the promoter region… Show more
“…Interestingly, almost two-thirds (64.1%) of these candidate nutrition-sensitive meQTLs were predicted to strongly alter the likelihood of TF binding 56,57 , although, a similar proportion was observed among putative nutrition-insensitive meQTLs (65.1%; Supplementary Data 7 and 8) and there was substantial overlap between the two sets of TFs. The ten (8.5%) TFs unique to the nutrition-sensitive meQTLs included the related TFs MLX and MLXIPL, which participate in pathways associated with nonalcoholic fatty liver disease (NAFLD) 58 . Given the modest samples sizes employed and a limited view of African genetic variation, however, it is likely that some of the nutrition-insensitive meQTLs could be misclassified and are really nutrition-sensitive, or that more complex mechanisms of activation in the context of severe malnutrition could differentiate the two datasets.Fig.…”
Edematous severe acute childhood malnutrition (edematous SAM or ESAM), which includes kwashiorkor, presents with more overt multi-organ dysfunction than non-edematous SAM (NESAM). Reduced concentrations and methyl-flux of methionine in 1-carbon metabolism have been reported in acute, but not recovered, ESAM, suggesting downstream DNA methylation changes could be relevant to differences in SAM pathogenesis. Here, we assess genome-wide DNA methylation in buccal cells of 309 SAM children using the 450 K microarray. Relative to NESAM, ESAM is characterized by multiple significantly hypomethylated loci, which is not observed among SAM-recovered adults. Gene expression and methylation show both positive and negative correlation, suggesting a complex transcriptional response to SAM. Hypomethylated loci link to disorders of nutrition and metabolism, including fatty liver and diabetes, and appear to be influenced by genetic variation. Our epigenetic findings provide a potential molecular link to reported aberrant 1-carbon metabolism in ESAM and support consideration of methyl-group supplementation in ESAM.
“…Interestingly, almost two-thirds (64.1%) of these candidate nutrition-sensitive meQTLs were predicted to strongly alter the likelihood of TF binding 56,57 , although, a similar proportion was observed among putative nutrition-insensitive meQTLs (65.1%; Supplementary Data 7 and 8) and there was substantial overlap between the two sets of TFs. The ten (8.5%) TFs unique to the nutrition-sensitive meQTLs included the related TFs MLX and MLXIPL, which participate in pathways associated with nonalcoholic fatty liver disease (NAFLD) 58 . Given the modest samples sizes employed and a limited view of African genetic variation, however, it is likely that some of the nutrition-insensitive meQTLs could be misclassified and are really nutrition-sensitive, or that more complex mechanisms of activation in the context of severe malnutrition could differentiate the two datasets.Fig.…”
Edematous severe acute childhood malnutrition (edematous SAM or ESAM), which includes kwashiorkor, presents with more overt multi-organ dysfunction than non-edematous SAM (NESAM). Reduced concentrations and methyl-flux of methionine in 1-carbon metabolism have been reported in acute, but not recovered, ESAM, suggesting downstream DNA methylation changes could be relevant to differences in SAM pathogenesis. Here, we assess genome-wide DNA methylation in buccal cells of 309 SAM children using the 450 K microarray. Relative to NESAM, ESAM is characterized by multiple significantly hypomethylated loci, which is not observed among SAM-recovered adults. Gene expression and methylation show both positive and negative correlation, suggesting a complex transcriptional response to SAM. Hypomethylated loci link to disorders of nutrition and metabolism, including fatty liver and diabetes, and appear to be influenced by genetic variation. Our epigenetic findings provide a potential molecular link to reported aberrant 1-carbon metabolism in ESAM and support consideration of methyl-group supplementation in ESAM.
“…Glucose induced L‐type pyruvate kinase (LPK) gene expression, regardless of insulin, in cultured hepatocytes (Doiron, Cuif, Kahn, & Diaz‐Guerra, ). ChREBP transcription factor seems a key player of carbohydrate‐induced transcriptional activity in liver (Jois & Sleeman, ; Uyeda, Yamashita, & Kawaguchi, ), but detailed mechanisms of this regulation are still to be fully described.…”
Section: Introductionmentioning
confidence: 99%
“…ChREBP transcription factor seems a key player of carbohydrateinduced transcriptional activity in liver (Jois & Sleeman, 2017;Uyeda, Yamashita, & Kawaguchi, 2002), but detailed mechanisms of this regulation are still to be fully described.…”
Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS2) catalyses the first step of ketogenesis and is critical in various metabolic conditions. Several nutrient molecules were able to differentially modulate HMGCS2 expression levels. Docosahexaenoic acid (DHA, C22:6, n-3), eicosapentaenoic acid (EPA, C20:5, n-3), arachidonic acid (AA, C20:4, n-6), and glucose increased HMGCS2 mRNA and protein levels in HepG2 hepatoma cells, while fructose decreased them. The effect of n-6 AA resulted significantly higher than that of n-3 PUFA, but when combined all these molecules were far less efficient. Insulin reduced HMGCS2 mRNA and protein levels in HepG2 cells, even when treated with PUFA and monosaccharides. Several nuclear receptors and transcription factors are involved in HMGCS2 expression regulation. While peroxysome proliferator activated receptor α (PPAR-α) agonist WY14643 increased HMGCS2 expression, this treatment was unable to affect PUFA-mediated regulation of HMGCS2 expression. Forkhead box O1 (FoxO1) inhibitor AS1842856 reduced HMGCS2 expression and suppressed induction promoted by fatty acids. Cells treatment with liver X receptor alpha (LXRα) agonist T0901317 reduced HMGCS2 mRNA, indicating a role for this transcription factor as suppressor of HMGCS2 gene. Previous observations already indicated HMGCS2 expression as possible nutrition status reference: our results show that several nutrients as well as specific nutritional related hormonal conditions are able to affect significantly HMGCS2 gene expression, indicating a relevant role for PUFA, which are mostly derived from nutritional intake. These insights into mechanisms of its regulation, specifically through nutrients commonly associated with disease risk, indicate HMGCS2 expression as possible reference marker of metabolic and nutritional status.
“…Unlike SREBP‐1, ChREBP transactivation is controlled by a nuclei‐cytoplasmic shuttling mechanism which depends on its phosphorylation status . Nuclear levels of ChREBP protein have been analyzed.…”
Section: Resultsmentioning
confidence: 99%
“…After feeding, xylulose‐5‐phosphate, produced by glucose metabolism through the pentose phosphate pathway, activates protein phosphatase 2A, which dephosphorylates ChREBP. Dephosphorylated ChREBP moves in the nucleus and induces the expression of the target genes .…”
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