Regulation of the expression of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene. Its role in the control of ketogenesis

Casals, Núria; Roca, Núria Bosch; Guerrero, Mario; Gil‐Gómez, Gabriel; Ayté, José; Ciudad, Carlos J.; Hegardt, Fausto G.

doi:10.1042/bj2830261

Cited by 79 publications

(76 citation statements)

References 25 publications

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“…In order to study the hormonal regulation of the gene, our group previously carried out several in-vivo experiments to study the influence of dibutyryl CAMP, insulin, dexamethasone, a diet of fat, diabetes and refeeding after 24 h of fasting on mRNA levels. These results showed that the mRNA levels are strongly influenced by these effectors (Casals et al, 1992).…”

Section: The Promoter and 5' Flanking Regionmentioning

confidence: 51%

“…Transient transfection experiments confirm the presence of elements involved in the CAMP, insulin, dexamethasone and fatty-acid response in the proximal 1149 bp of the promoter region. These observations correlate with the regulation of the active enzyme by glucagon (Siess et al 1980), insulin (Quant et al, 1989) and with the in-vivo multihormonal regulation of the mRNA levels (Casals et al 1992). Further work is required in order to assign these regulatory elements to definite nucleotide sequences in the mitochondrial HMG-CoA promoter.…”

Section: The Promoter and 5' Flanking Regionmentioning

confidence: 68%

“…The levels of mitochondrial HMG-CoA-synthase mRNA are accurately regulated by different hormones and metabolic situations (Casals et al, 1992). Thus, the amounts of HMGCoA-synthase mRNA are rapidly changed in response to cyclic AMP, insulin, dexamethasone and refeeding.…”

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confidence: 99%

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The rat mitochondrial 3‐hydroxy‐3‐methylglutaryl‐coenzyme‐A‐synthase gene contains elements that mediate its multihormonal regulation and tissue specificity

Gil‐Gómez¹,

Ayté²,

Hegardt³

1993

European Journal of Biochemistry

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Mitochondrial 3‐hydroxy‐3‐methylglutaryl‐coenzyme‐A (HMG‐CoA) synthase, a liver‐specific enzyme, is a constituent of the HMG‐CoA cycle responsible for ketone‐body synthesis. We report the isolation and characterization of genomic clones that encompass the gene for rat mitochondrial HMG‐CoA synthase. The gene spans at least 24 kbp and contains ten exons and nine introns. The 5′ flanking region of the gene has also been cloned and characterized. Exon 1 contains the untranslated sequence of the transcript, extending downstream to enclose the coding region for the putative mitochondrial‐targeting signal (35 amino acids). The 1149‐bp proximal region of the transcription start point permits transcription of a reporter gene in transfected hepatoma cells but not in an extrahepatic cell line, confirming the function of the promoter. A truncated construct of 142 bp is still able to promote transcription in hepatoma cells, suggesting the presence of liver‐specific enhancer elements in the proximal promoter region. The 5′ flanking region contains typical promoter elements, including a TATA box and several putative recognition sequences for transcription factors involved in controlling both basal‐level and hormone‐modulated transcription rates. Furthermore, the presence in the mitochondrial HMG‐CoA‐synthase promoter of cis‐elements, responsible for the multihormonal regulation of transcription, is supported by transient transfection experiments.

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Section: The Promoter and 5' Flanking Regionmentioning

confidence: 51%

Section: The Promoter and 5' Flanking Regionmentioning

confidence: 68%

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The rat mitochondrial 3‐hydroxy‐3‐methylglutaryl‐coenzyme‐A‐synthase gene contains elements that mediate its multihormonal regulation and tissue specificity

Gil‐Gómez¹,

Ayté²,

Hegardt³

1993

European Journal of Biochemistry

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“…This suggests that as a consequence of relatively low glucocorticoid levels, hepatic glucocorticoid receptor activity was decreased in SR-BI-deficient mice. Furthermore, a significant decrease (243% to 265%) was observed in the hepatic mRNA expression of genes that are stimulated by the glucocorticoid receptor and are involved in hepatic lipid and glucose metabolism, such as cholesterol 7a-hydroxylase (CYP7A1) (20), HMG-CoA synthase (HMGCS) (21), and apolipoprotein A-IV (ApoA-IV) (22) (Fig. 5).…”

Section: Resultsmentioning

confidence: 99%

Absence of HDL cholesteryl ester uptake in mice via SR-BI impairs an adequate adrenal glucocorticoid-mediated stress response to fasting

Hoekstra¹,

Meurs²,

Koenders³

et al. 2008

Journal of Lipid Research

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Receptor-mediated cholesterol uptake has been suggested to play a role in maintaining the adrenal intracellular free cholesterol pool and the ability to produce hormones. Therefore, in the current study, we evaluated the importance of scavenger receptor class B type I (SR-BI)-mediated cholesteryl ester uptake from HDL for adrenal glucocorticoid hormone synthesis in vivo. No difference was observed in the plasma level of corticosterone between SR-BI-deficient and wild-type mice under ad libitum feeding conditions. Overnight fasting (?16 h) stimulated the plasma level of corticosterone by 2-fold in wild-type mice. In contrast, no effect of fasting on plasma corticosterone levels was observed in SR-BI-deficient mice, leading to a 44% lower plasma corticosterone level compared with their wild-type littermate controls. In parallel, an almost complete depletion of lipid stores in the adrenal cortex of fasted SR-BIdeficient mice was observed. Plasma adrenocorticotropic hormone levels were increased by 5-fold in fasted SR-BIdeficient mice. SR-BI deficiency induced marked changes in the hepatic expression of the glucocorticoid-responsive genes cholesterol 7a-hydroxylase, HMG-CoA synthase, apolipoprotein A-IV, corticosteroid binding globulin, interleukin-6, and tumor necrosis factor-a, which coincided with a 42% decreased plasma glucose level under fasting conditions. In conclusion, we show that the absence of adrenal HDL cholesteryl ester uptake in SR-BI-deficient mice impairs the adrenal glucocorticoid-mediated stress response to fasting as a result of adrenal glucocorticoid insufficiency and attenuated liver glucocorticoid receptor signaling, leading to hypoglycemia under fasting conditions.-Hoekstra, M., I. Meurs, M. Koenders, R. Out, R. B. Hildebrand, J. K. Kruijt, M. Van Eck, and T. J. C. Van Berkel. Absence of HDL cholesteryl ester uptake in mice via SR-BI impairs an adequate adrenal glucocorticoid-mediated stress response to fasting. J. Lipid Res. 2008. 49: 738-745.

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“…It has been suggested that intramitochondrial 3-hydroxy-3-methylglutaryl-CoA (mHMG-CoA) synthase becomes an important locus of control under these conditions [71,72]. Insulin treatment of starved or diabetic rats results in the rapid decline in the hepatic concentration of mHMG-CoA synthase mRNA and protein [72,73]. In addition, the enzyme reverts to the succinylated (inhibited) state during refeeding of starved rats [74].…”

Section: Enzymes Involved In the Partitioning Of Fatty Acids Between mentioning

confidence: 99%

Role of insulin in hepatic fatty acid partitioning: emerging concepts

Zammit

1996

Biochemical Journal

114

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Regulation of the expression of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene. Its role in the control of ketogenesis

Cited by 79 publications

References 25 publications

The rat mitochondrial 3‐hydroxy‐3‐methylglutaryl‐coenzyme‐A‐synthase gene contains elements that mediate its multihormonal regulation and tissue specificity

The rat mitochondrial 3‐hydroxy‐3‐methylglutaryl‐coenzyme‐A‐synthase gene contains elements that mediate its multihormonal regulation and tissue specificity

Absence of HDL cholesteryl ester uptake in mice via SR-BI impairs an adequate adrenal glucocorticoid-mediated stress response to fasting

Role of insulin in hepatic fatty acid partitioning: emerging concepts

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