scholarly journals Hepatic Glucokinase Is Required for the Synergistic Action of ChREBP and SREBP-1c on Glycolytic and Lipogenic Gene Expression

2004 ◽  
Vol 279 (19) ◽  
pp. 20314-20326 ◽  
Author(s):  
Renaud Dentin ◽  
Jean-Paul Pégorier ◽  
Fadila Benhamed ◽  
Fabienne Foufelle ◽  
Pascal Ferré ◽  
...  
Keyword(s):  
Gene Expression ◽  
Glucose Metabolism ◽  
Binding Protein ◽  
Synergistic Action ◽  
Glucose Effect ◽  
Lipogenic Gene ◽  
Lipogenic Genes ◽  
Lipogenic Gene Expression ◽  
Spot 14 ◽  
Element Binding Protein

Hepatic glucokinase (GK) catalyzes the phosphorylation of glucose to glucose 6-phosphate (G6P), a step which is essential for glucose metabolism in liver as well as for the induction of glycolytic and lipogenic genes. The sterol regulatory element-binding protein-1c (SREBP-1c) has emerged as a major mediator of insulin action on hepatic gene expression, but the extent to which its transcriptional effect is caused by an increased glucose metabolism remains unclear. Through the use of hepatic GK knockout mice (hGK-KO) we have shown that the acute stimulation by glucose ofl-pyruvate kinase (l-PK), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), andSpot 14genes requires GK expression. To determine whether the effect of SREBP-1c requires GK expression and subsequent glucose metabolism, a transcriptionally active form of SREBP-1c was overexpressed bothin vivoand in primary cultures of control and hGK-KO hepatocytes. Our results demonstrate that the synergistic action of SREBP-1c and glucose metabolism via GK is necessary for the maximal induction ofl-PK, ACC, FAS, andSpot 14gene expression. Indeed, in hGK-KO hepatocytes overexpressing SREBP-1c, the effect of glucose on glycolytic and lipogenic genes is lost because of the impaired ability of these hepatocytes to efficiently metabolize glucose, despite a marked increase in lowKmhexokinase activity. Our studies also reveal that the loss of glucose effect observed in hGK-KO hepatocytes is associated with a decreased in the carbohydrate responsive element-binding protein (ChREBP) gene expression, a transcription factor suggested to mediate glucose signaling in liver. DecreasedChREBPgene expression, achieved using small interfering RNA, results in a loss of glucose effect on endogenous glycolytic (l-PK) and lipogenic (FAS, ACC) gene expression, thereby demonstrating the direct implication of ChREBP in glucose action. Together these results support a model whereby both SREBP-1c and glucose metabolism, acting via ChREBP, are necessary for the dietary induction of glycolytic and lipogenic gene expression in liver.

scholarly journals Carbohydrate-response-element-binding protein (ChREBP) and not the liver X receptor α (LXRα) mediates elevated hepatic lipogenic gene expression in a mouse model of glycogen storage disease type 1

2010 ◽  
Vol 432 (2) ◽  
pp. 249-254 ◽  
Author(s):  
Aldo Grefhorst ◽  
Marijke Schreurs ◽  
Maaike H. Oosterveer ◽  
Victor A. Cortés ◽  
Rick Havinga ◽  
...  
Keyword(s):  
Gene Expression ◽  
Binding Protein ◽  
Glycogen Storage Disease Type ◽  
Glycogen Storage ◽  
Hepatic Glycogen ◽  
Lipogenic Gene ◽  
Lipogenic Gene Expression ◽  
Liver X Receptor Α ◽  
Element Binding Protein

GSD-1 (glycogen storage disease type 1) is caused by an inherited defect in glucose-6-phosphatase activity, resulting in a massive accumulation of hepatic glycogen content and an induction of de novo lipogenesis. The chlorogenic acid derivative S4048 is a pharmacological inhibitor of the glucose 6-phosphate transporter, which is part of glucose-6-phosphatase, and allows for mechanistic studies concerning metabolic defects in GSD-1. Treatment of mice with S4048 resulted in an ~60% reduction in blood glucose, increased hepatic glycogen and triacylglycerol (triglyceride) content, and a markedly enhanced hepatic lipogenic gene expression. In mammals, hepatic expression of lipogenic genes is regulated by the co-ordinated action of the transcription factors SREBP (sterol-regulatory-element-binding protein)-1c, LXRα (liver X receptor α) and ChREBP (carbohydrate-response-element-binding protein). Treatment of Lxra−/− mice and Chrebp−/− mice with S4048 demonstrated that ChREBP, but not LXRα, mediates the induction of hepatic lipogenic gene expression in this murine model of GSD-1. Thus ChREBP is an attractive target to alleviate derangements in lipid metabolism observed in patients with GSD-1.

scholarly journals Human Sterol Regulatory Element-Binding Protein 1a Contributes Significantly to Hepatic Lipogenic Gene Expression

2015 ◽  
Vol 35 (2) ◽  
pp. 803-815 ◽  
Author(s):  
Andreas Bitter ◽  
Andreas K. Nüssler ◽  
Wolfgang E. Thasler ◽  
Kathrin Klein ◽  
Ulrich M. Zanger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Liver ◽  
Target Genes ◽  
Binding Protein ◽  
Regulatory Element ◽  
Lipogenic Gene ◽  
Knock Down ◽  
Lipogenic Gene Expression ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Background/Aims: Sterol regulatory element-binding protein (SREBP) 1, the master regulator of lipogenesis, was shown to be associated with non-alcoholic fatty liver disease, which is attributed to its major isoform SREBP1c. Based on studies in mice, the minor isoform SREBP1a is regarded as negligible for hepatic lipogenesis. This study aims to elucidate the expression and functional role of SREBP1a in human liver. Methods: mRNA expression of both isoforms was quantified in cohorts of human livers and primary human hepatocytes. Hepatocytes were treated with PF-429242 to inhibit the proteolytic activation of SREBP precursor protein. SREBP1a-specifc and pan-SREBP1 knock-down were performed by transfection of respective siRNAs. Lipogenic SREBP-target gene expression was analyzed by real-time RT-PCR. Results: In human liver, SREBP1a accounts for up to half of the total SREBP1 pool. Treatment with PF-429242 indicated SREBP-dependent auto-regulation of SREBP1a, which however was much weaker than of SREBP1c. SREBP1a-specifc knock-down also reduced significantly the expression of SREBP1c and of SREBP-target genes. Regarding most SREBP-target genes, simultaneous knock-down of both isoforms resulted in effects of only similar extent as SREBP1a-specific knock-down. Conclusion: We here showed that SREBP1a is significantly contributing to the human hepatic SREBP1 pool and has a share in human hepatic lipogenic gene expression.

scholarly journals Cell-Type–Specific, Ketohexokinase-Dependent Induction by Fructose of Lipogenic Gene Expression in Mouse Small Intestine

2020 ◽  
Vol 150 (7) ◽  
pp. 1722-1730 ◽  
Author(s):  
Arwa Al-Jawadi ◽  
Chirag R Patel ◽  
Reilly J Shiarella ◽  
Emmanuellie Romelus ◽  
Madelyn Auvinen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Metabolic Diseases ◽  
Free Access ◽  
Wild Type ◽  
Cell Type ◽  
Lipogenic Gene ◽  
Lipogenic Genes ◽  
Lipogenic Gene Expression ◽  
Small Intestinal

ABSTRACT Background High intakes of fructose are associated with metabolic diseases, including hypertriglyceridemia and intestinal tumor growth. Although small intestinal epithelia consist of many different cell types, express lipogenic genes, and convert dietary fructose to fatty acids, there is no information on the identity of the cell type(s) mediating this conversion and on the effects of fructose on lipogenic gene expression. Objectives We hypothesized that fructose regulates the intestinal expression of genes involved in lipid and apolipoprotein synthesis, that regulation depends on the fructose transporter solute carrier family 2 member a5 [Slc2a5 (glucose transporter 5)] and on ketohexokinase (Khk), and that regulation occurs only in enterocytes. Methods We compared lipogenic gene expression among different organs from wild-type adult male C57BL mice consuming a standard vivarium nonpurified diet. We then gavaged twice daily for 2.5 d fructose or glucose solutions (15%, 0.3 mL per mouse) into wild-type, Slc2a5-knockout (KO), and Khk-KO mice with free access to the nonpurified diet and determined expression of representative lipogenic genes. Finally, from mice fed the nonpurified diet, we made organoids highly enriched in enterocyte, goblet, Paneth, or stem cells and then incubated them overnight in 10 mM fructose or glucose. Results Most lipogenic genes were significantly expressed in the intestine relative to the kidney, liver, lung, and skeletal muscle. In vivo expression of Srebf1, Acaca, Fasn, Scd1, Dgat1, Gk, Apoa4, and Apob mRNA and of Scd1 protein increased (P < 0.05) by 3- to 20-fold in wild-type, but not in Slc2a5-KO and Khk-KO, mice gavaged with fructose. In vitro, Slc2a5- and Khk-dependent, fructose-induced increases, which ranged from 1.5- to 4-fold (P < 0.05), in mRNA concentrations of all these genes were observed only in organoids enriched in enterocytes. Conclusions Fructose specifically stimulates expression of mouse small intestinal genes for lipid and apolipoprotein synthesis. Secretory and stem cells seem incapable of transport- and metabolism-dependent lipogenesis, occurring only in absorptive enterocytes.

scholarly journals ADD1/SREBP-1c Is Required in the Activation of Hepatic Lipogenic Gene Expression by Glucose

1999 ◽  
Vol 19 (5) ◽  
pp. 3760-3768 ◽  
Author(s):  
Marc Foretz ◽  
Corinne Pacot ◽  
Isabelle Dugail ◽  
Patricia Lemarchand ◽  
Colette Guichard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid Synthase ◽  
Primary Cultures ◽  
Rat Hepatocytes ◽  
Dominant Negative ◽  
Temporal Association ◽  
Lipogenic Gene ◽  
Lipogenic Genes ◽  
Lipogenic Gene Expression ◽  
Carbohydrate Feeding

ABSTRACT The transcription of genes encoding proteins involved in the hepatic synthesis of lipids from glucose is strongly stimulated by carbohydrate feeding. It is now well established that in the liver, glucose is the main activator of the expression of this group of genes, with insulin having only a permissive role. While ADD1/SREBP-1 has been implicated in lipogenic gene expression through temporal association with food intake and ectopic gain-of-function experiments, no genetic evidence for a requirement for this factor in glucose-mediated gene expression has been established. We show here that the transcription of ADD1/SREBP-1c in primary cultures of hepatocytes is controlled positively by insulin and negatively by glucagon and cyclic AMP, establishing a link between this transcription factor and carbohydrate availability. Using adenovirus-mediated transfection of a powerful dominant negative form of ADD1/SREBP-1c in rat hepatocytes, we demonstrate that this factor is absolutely necessary for the stimulation by glucose of l-pyruvate kinase, fatty acid synthase, S14, and acetyl coenzyme A carboxylase gene expression. These results demonstrate that ADD1/SREBP-1c plays a crucial role in mediating the expression of lipogenic genes induced by glucose and insulin.

scholarly journals Trans-10, cis-12 conjugated linoleic acid reduces milk fat content and lipogenic gene expression in the mammary gland of sows without altering litter performance

2019 ◽  
Vol 123 (6) ◽  
pp. 610-618 ◽  
Author(s):  
E. C. Sandri ◽  
K. J. Harvatine ◽  
D. E. Oliveira
Keyword(s):  
Gene Expression ◽  
Mammary Gland ◽  
Fatty Acid ◽  
Linoleic Acid ◽  
Conjugated Linoleic Acid ◽  
Milk Fat ◽  
Fat Content ◽  
Lipogenic Gene ◽  
Lipogenic Genes ◽  
Lipogenic Gene Expression

AbstractTrans-10, cis-12 conjugated linoleic acid (CLA) decreases milk fat synthesis in lactating sows and involves, at least in part, the down-regulation of lipogenic genes. The objective was to evaluate the effect of CLA on milk composition and lipogenic gene expression. Twenty multiparous sows were randomly assigned to one of the two treatments for 18 d (from day 7 to day 25 of lactation): (1) control (no CLA added) and (2) 1 % of CLA mixed into the ration. CLA treatment decreased milk fat and protein content by 20 % (P = 0·004) and 11 % (P = 0·0001), respectively. However, piglet weight did not differ between treatments (P = 0·60). Dietary CLA increased the concentration of SFA in milk fat by 16 % (P < 0·0001) and decreased MUFA by 17·6 % (P < 0·0001). In the mammary gland, CLA reduced gene expression of acetyl-CoA carboxylase-α by 37 % (P = 0·003), fatty acid synthase by 64 % (P = 0·002), stearoyl-CoA desaturase 1 by 52 % (P = 0·003), lipoprotein lipase by 26 % (P = 0·03), acyl glycerol phosphate acyltransferase 6 by 15 % (P = 0·02) and diacylglycerol acyltransferase 1 by 27 % (P = 0·02), whereas the expression of fatty acid binding protein 3 was not altered by CLA treatment (P = 0·09). Mammary expression of casein-β and α-lactalbumin was reduced by CLA by 68 % (P = 0·0004) and 62 % (P = 0·005), respectively. Additionally, CLA had no effect on the expression of lipogenic genes evaluated in adipose tissue. In summary, CLA reduced milk fat content without negatively affecting litter performance and it affected mammary expression of genes involved in all lipogenic pathways studied.

scholarly journals Coumarin attenuates hepatic steatosis by down-regulating lipogenic gene expression in mice fed a high-fat diet

2013 ◽  
Vol 109 (9) ◽  
pp. 1590-1597 ◽  
Author(s):  
Min Young Um ◽  
Mi Kyeong Moon ◽  
Jiyun Ahn ◽  
Tae Youl Ha
Keyword(s):  
Gene Expression ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Fatty Acid Synthase ◽  
Binding Protein ◽  
Regulatory Element ◽  
Thiobarbituric Acid Reactive Substance ◽  
High Fat ◽  
Lipogenic Gene ◽  
Lipogenic Gene Expression

Coumarin is a natural compound abundant in plant-based foods such as citrus fruits, tomatoes, vegetables and green tea. Although coumarin has been reported to exhibit anti-coagulant, anti-inflammation and cholesterol-lowering properties, the effect of coumarin on hepatic lipid metabolism remains unclear. In the present study, we evaluated the ability of coumarin to protect against hepatic steatosis associated with a high-fat diet (HFD) and investigated potential mechanisms underlying this effect. C57BL/6J mice were fed a normal diet, HFD and HFD containing 0·05 % courmarin for 8 weeks. The present results showed that coumarin reduced weight gain and abdominal fat mass in mice fed the HFD for 8 weeks (P< 0·05). Coumarin also significantly reduced the HFD-induced elevation in total cholesterol, apoB, leptin and insulin (P< 0·05). In the liver of HFD-fed mice, coumarin significantly reduced total lipids, TAG and cholesterol (38, 22 and 9 % reductions, respectively; P< 0·05), as well as lipid droplet number and size. Additionally, thiobarbituric acid-reactive substance levels, as an indicator of hepatic steatosis, were attenuated by coumarin (P< 0·05). Finally, coumarin suppressed the HFD-induced up-regulation in fatty acid synthase (FAS) activity, and the expression of sterol regulatory element-binding protein-1, FAS, acetyl-CoA carboxylase 1, PPARγ and CCAAT/enhancer-binding protein-α in the liver. Taken together, these results demonstrate that coumarin could prevent HFD-induced hepatic steatosis by regulating lipogenic gene expression, suggesting potential targets for preventing hepatic steatosis.

scholarly journals Association of a polymorphism in SREBP1 with fatty acid composition and lipogenic gene expression in beef cattle breeds

2019 ◽  
Author(s):  
David Gamarra ◽  
Noelia Aldai ◽  
Aisaku Arakawa ◽  
Marian M. de Pancorbo ◽  
Masaaki Taniguchi
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Regulatory Element ◽  
Northern Spain ◽  
Lipogenic Gene ◽  
Lipogenic Genes ◽  
Fa Composition ◽  
Element Binding Protein ◽  
Definition Of ◽  
Lipogenic Gene Transcription

Abstract Background Sterol regulatory element-binding protein 1 (SREBP1) plays an important role in the lipogenesis and fatty acid (FA) composition in fat cells and is consequently considered to influence the nutritional quality of beef. SREBP1 regulates lipogenic gene transcription including stearoyl-CoA desaturases (SCDs) that are responsible for unsaturation of FAs. Therefore, we performed phylogenetic analysis on SREBP1 gene sequences, including 84 bp-indel, among mammals to elucidate the evolutionary importance of this polymorphism and possible effect in the FA composition. Additionally, we analyzed the association between the indel, FA composition, and gene expression of SREBP1 and SCDs in backfat of several commercial type beef breeds in northern Spain (Pirenaica, Salers and Holstein-Friesian).Results In ruminants, the indel region was relatively highly conserved in comparison with the rest of intron 5 sequence or mRNA of SREBP1, suggesting the potential functionality throughout evolution. We applied the definition of the insertion and deletion of 84 bp in intron 5: S (Short) and L (Long) alleles, respectively. Then, we figured the indel is associated with saturated FA (SFA) and several polyunsaturated FA (PUFA) depending on commercial type, specifically Pirenaica bulls, whose SS/SL genotype has been associated with a higher content of 18:0, n-3 and 18:3n-3 (p < 0.05). In Salers, S allele showed the highest frequency (0.385) among all breeds, while SS genotype had high positive correlations between SREBP1 gene expression and UFA contents. Significant correlations between SCD1 and SFAs (16:0) in SL genotype of Pirenaica bulls, but also 9c-16:1 in Pirenaica breed (p < 0.05), suggests a differential relationship between SCD1 and 16:0/9c-16:1 FA contents depending on the indel genotype in this breed. Overall, SS and SS/SL genotypes had a positive correlation between SCD5 and 18:0 (p < 0.05) and a negative correlation between SCD5 and 9c-18:1 (p > 0.05).Conclusions These results suggest that the indel is associated with SFA and PUFA content depending on commercial type. Moreover, the correlations between lipogenic genes (SREBP1 and SCDs) with 16:0 and 9c-16:1, but also 18:0 and 9c-18:1, seems to be attributed to the indel genotype. These findings are useful for beef/dairy breeding to supply nutritionally favorable products.

scholarly journals Nutritional regulation of renal lipogenic factor expression in mice: comparison to regulation in the liver and skeletal muscle

2017 ◽  
Vol 313 (4) ◽  
pp. F887-F898 ◽  
Author(s):  
Suk-Jeong Kim ◽  
Ji-Eun Kim ◽  
Yong-Woon Kim ◽  
Jong-Yeon Kim ◽  
So-Young Park
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Nutritional Regulation ◽  
Obese Mice ◽  
Lipogenic Gene ◽  
Protein Levels ◽  
Lipogenic Gene Expression ◽  
Element Binding Protein ◽  
Fasting And Refeeding ◽  
Renal Expression

Regulation of lipogenesis by pathophysiological factors in the liver and skeletal muscle is well understood; however, regulation in the kidney is still unclear. To elucidate nutritional regulation of lipogenic factors in the kidney, we measured the renal expression of lipogenic transcriptional factors and enzymes during fasting and refeeding in chow-fed and high-fat-fed mice. We also examined the regulatory effect of the liver X receptor (LXR) on the expression of lipogenic factors. The renal gene expression of sterol regulatory element-binding protein (SREBP)-1c and fatty acid synthase (FAS) was reduced by fasting for 48 h and restored by refeeding, whereas the mRNA levels of forkhead box O (FOXO)1/3 were increased by fasting and restored by refeeding. Accordingly, protein levels of SREBP-1, FAS, and phosphorylated FOXO1/3 were reduced by fasting and restored by refeeding. The patterns of lipogenic factors expression in the kidney were similar to those in the liver and skeletal muscle. However, this phasic regulation of renal lipogenic gene expression was blunted in diet-induced obese mice. LXR agonist TO901317 increased the lipogenic gene expression and the protein levels of SREBP-1 precursor and FAS but not nuclear SREBP-1. Moreover, increases in insulin-induced gene mRNA and nuclear carbohydrate-responsive element binding protein (ChREBP) levels were observed in the TO901317-treated mice. These results suggest that the kidney shows flexible suppression and restoration of lipogenic factors following fasting and refeeding in lean mice, but this is blunted in obese mice. LXR is involved in the renal expression of lipogenic enzymes, and ChREBP may mediate the response.

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