Tissue-specific Expression and Dietary Regulation of Chimeric Mitochondrial 3-Hydroxy-3-methylglutaryl Coenzyme A Synthase/Human Growth Hormone Gene in Transgenic Mice

Serra, Dolors; Fillat, Cristina; Matas, Raquel Burggraaf-Sánchez de las; Bosch, Fátima; Hegardt, Fausto G.

doi:10.1074/jbc.271.13.7529

Cited by 8 publications

(9 citation statements)

References 23 publications

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“…displaying constant mHMGCoA synthase mRNA concentrations in the colonic epithelium over a 2‐day period of fasting, characterized by profound changes in plasma insulin and glucagon concentrations. This result confirms that the expression of the mHMGCoA synthase in the colon and in the liver is differentially regulated [29].…”

Section: Discussionsupporting

confidence: 83%

Expression of mitochondrial HMGCoA synthase and glutaminase in the colonic mucosa is modulated by bacterial species

Cherbuy

Andrieux

Honvo-Houeto

et al. 2003

European Journal of Biochemistry

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The expression of the colonic mitochondrial 3-hydroxy 3-methyl glutaryl CoA (mHMGCoA) synthase, a key control site of ketogenesis from butyrate, is lower in germ-free (GF) than in conventional (CV) rats. In contrast, the activity of glutaminase is higher. The objective of this study was to investigate whether the intestinal flora can affect gene expression through short chain fatty acid (SCFA) and butyrate production. GF rats were inoculated with a conventional flora (Ino-CV) or with a bacterial strain producing butyrate (Clostridium paraputrificum, Ino-Cp) or not (Bifidobacterium breve, Ino-Bb). In the Ino-CV rats, mHMGCoA synthase expression was restored to the CV values 2 days after the inoculation, i.e. concomitantly with SCFA production. In the Ino-Cp group, but not in the InoBb group, mHMGCoA synthase and glutaminase were expressed at the level observed in the CV rats. These data suggest that the intestinal flora, through butyrate production, could control the expression of colonic mHMGCoA synthase and glutaminase. These modifications in gene expression by butyrate in vivo seem unrelated to a modification of histone acetylation.

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Section: Discussionsupporting

confidence: 83%

Expression of mitochondrial HMGCoA synthase and glutaminase in the colonic mucosa is modulated by bacterial species

Cherbuy

Andrieux

Honvo-Houeto

et al. 2003

European Journal of Biochemistry

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“…The occurrence of a nuclear receptor responsive element (NRRE), which binds peroxisome-proliferator-activated receptor (PPAR), chicken ovalbumin upstream promoter transcription factor (COUP-TF) and hepatocyte nuclear factor-4 (HNF-4), has been demonstrated (see below) [11,81,82], in addition to the cAMP regulatory element (CRE) binding site (A. Eckers, C. Caudevilla, G. Asins, F. G. Hegardt and D. Serra, unpublished work). Some of these sequences present in the rat gene are also observed in the human [80] and pig [83] mitochondrial HMG-CoA synthase gene 5h flanking regions.…”

Section: Isolation Of Mitochondrial Hmg-coa Synthase Genesmentioning

confidence: 90%

“…Comparison of this 5h flanking region with the canonical sequences of several cis elements shows that several known sequences appear in this 5h flanking region (Table 1). Transfection studies in HepG2 cells [7] and in transgenic mice [80] suggest multi-hormonal regulation of gene transcription. The occurrence of a nuclear receptor responsive element (NRRE), which binds peroxisome-proliferator-activated receptor (PPAR), chicken ovalbumin upstream promoter transcription factor (COUP-TF) and hepatocyte nuclear factor-4 (HNF-4), has been demonstrated (see below) [11,81,82], in addition to the cAMP regulatory element (CRE) binding site (A. Eckers, C. Caudevilla, G. Asins, F. G. Hegardt and D. Serra, unpublished work).…”

Section: Isolation Of Mitochondrial Hmg-coa Synthase Genesmentioning

confidence: 99%

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: a control enzyme in ketogenesis

Hegardt

1999

Biochemical Journal

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294

218

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Cytosolic and mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthases were first recognized as different chemical entities in 1975, when they were purified and characterized by Lane's group. Since then, the two enzymes have been studied extensively, one as a control site of the cholesterol biosynthetic pathway and the other as an important control site of ketogenesis. This review describes some key developments over the last 25 years that have led to our current understanding of the physiology of mitochondrial HMG-CoA synthase in the HMG-CoA pathway and in ketogenesis in the liver and small intestine of suckling animals. The enzyme is regulated by two systems: succinylation and desuccinylation in the short term, and transcriptional regulation in the long term. Both control mechanisms are influenced by nutritional and hormonal factors, which explains the incidence of ketogenesis in diabetes and starvation, during intense lipolysis, and in the foetal-neonatal and suckling-weaning transitions. The DNA-binding properties of the peroxisome-proliferator-activated receptor and other transcription factors on the nuclear-receptor-responsive element of the mitochondrial HMG-CoA synthase promoter have revealed how ketogenesis can be regulated by fatty acids. Finally, the expression of mitochondrial HMG-CoA synthase in the gonads and the correction of auxotrophy for mevalonate in cells deficient in cytosolic HMG-CoA synthase suggest that the mitochondrial enzyme may play a role in cholesterogenesis in gonadal and other tissues.

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“…To explore the control of the HMGCS2 gene, we examined its transcriptional regulation. Transient transfection experiments and testing of transgenic mice have revealed that a 1149 bp fragment of the 5h-flanking region contains the elements responsible for the multi-hormonal regulation of transcription of this gene [10,11]. The HMGCS2 gene promoter contains a peroxisome proliferator-activated receptor-responsive element, and the activation of HMGCS2 gene expression by fatty acids may be mediated by this receptor [12].…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by insulin: the role of the forkhead transcription factor FKHRL1

Nadal

Marrero

Haro

2002

Biochemical Journal

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Normal physiological responses to carbohydrate shortages cause the liver to increase the production of ketone bodies from the acetyl-CoA generated from fatty acid oxidation. This allows the use of ketone bodies for energy, thereby preserving the limited glucose for use by the brain. This adaptative response is switched off by insulin rapidly inhibiting the expression of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS2) gene, which is a key control site of ketogenesis. We decided to investigate the molecular mechanism of this inhibition. In the present study, we show that FKHRL1, a member of the forkhead in rhabdosarcoma (FKHR) subclass of the Fox family of transcription factors, stimulates transcription from transfected 3-hydroxy-3-methylglutaryl-CoA synthase promoter-luciferase reporter constructs, and that this stimulation is repressed by insulin. An FKHRL1-responsive sequence AAAAATA, located 211 bp upstream of the HMGCS2 gene transcription start site, was identified by deletion analysis. It binds FKHRL1 in vivo and in vitro and confers FKHRL1 responsiveness on homologous and heterologous promoters. If it is mutated, it partially blocks the effect of insulin in HepG2 cells, both in the absence and presence of overexpressed FKHRL1. These results suggest that FKHRL1 contributes to the regulation of HMGCS2 gene expression by insulin.

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Tissue-specific Expression and Dietary Regulation of Chimeric Mitochondrial 3-Hydroxy-3-methylglutaryl Coenzyme A Synthase/Human Growth Hormone Gene in Transgenic Mice

Cited by 8 publications

References 23 publications

Expression of mitochondrial HMGCoA synthase and glutaminase in the colonic mucosa is modulated by bacterial species

Expression of mitochondrial HMGCoA synthase and glutaminase in the colonic mucosa is modulated by bacterial species

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: a control enzyme in ketogenesis

Down-regulation of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by insulin: the role of the forkhead transcription factor FKHRL1

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