Induction of Thermogenic Enzymes by DHEA and Its Metabolites

Lardy, Henry A.; Kneer, Nancy; Bellei, Monica; Bobyleva, Valentina

doi:10.1111/j.1749-6632.1995.tb17380.x

Cited by 28 publications

(7 citation statements)

References 30 publications

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“…These differences, and the fact that the human 11␤-HSD1 functions both as an oxido-reductase and an epimerase with admission of several steroid types as substrates, may help in the assessment of the exact mechanism of its activity and of the spatial configuration at its active site. On the other hand, and with regard to the EpiA derivatives studied here, the implications of our findings in the metabolic regulation of the 11␤-HSD1-mediated cortisol-cortisone oxido-reduction are dubious for the following reasons: (i) because of its conversion to the sulfate derivative, EpiA circulating levels in human adults are very low [17], and the K cat /K M ratio for its 7␣-hydroxylation is one order of magnitude lower than for DHEA [1]; (ii) the once produced 7␣-hydroxy-EpiA is rapidly excreted under sulfate form [18]; (iii) the reductive action of the 11␤-HSD1 in tissues is favored by their predominant NADPH content [19,20] and cortisone reduction only could be inhibited by the putative 7-oxo-EpiA under these conditions. These considerations lead to conclude that the 7␣-and 7␤-hydroxy-EpiA concentrations required for inhibition may never be reached and that these steroid may not be involved in the native anti-glucocorticoid paradigm [21].…”

Section: Discussionmentioning

confidence: 99%

7α- and 7β-hydroxy-epiandrosterone as substrates and inhibitors for the human 11β-hydroxysteroid dehydrogenase type 1

Hennebert¹,

Pernelle²,

Ferroud³

et al. 2007

The Journal of Steroid Biochemistry and Molecular Biology

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Section: Discussionmentioning

confidence: 99%

7α- and 7β-hydroxy-epiandrosterone as substrates and inhibitors for the human 11β-hydroxysteroid dehydrogenase type 1

Hennebert¹,

Pernelle²,

Ferroud³

et al. 2007

The Journal of Steroid Biochemistry and Molecular Biology

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“…When administered in the food of rats, these steroids induced a significantly increased the activity of the malic enzyme and sn-glycerol-3-phosphate dehydrogenase of the liver. These enzymes are involved in the electron transport from the tricarboxylic cycle, and generate a large part of the cellular NADPH [96]. Whether these enzyme inductions resulted from a direct action by the 7-oxygenated steroids or from their anti-GC effect in the liver of the living rat has not been established yet.…”

Section: The Paradigm: Integrative Prospectsmentioning

confidence: 95%

“…6, we suggest that the activity of 11␤-HSD1 mainly depends on two factors: the availability of 7-hydroxylated DHEA metabolites and the cellular NADPH/NADP + ratio. The liver is known to contain a large amount of NADPH [96] and this extends to other target organs of GCs such as the skin and brain [72]. These Fig.…”

Section: The Anti-gc Mechanism: a Metabolic Fine Tuning Processmentioning

confidence: 99%

“…The NADP + -dependent conversion of 7␣-hydroxy-DHEA into 7-oxo-DHEA by 11␤-HSD1 was achieved [66,67] and is reversible provided that NADPH is made available to 11␤-HSD1. As the NADPH in the liver, skin and brain far exceeds the NADP + form [71,72], inactive GCs are mostly activated in these tissues by the NADPH-dependent 11␤-HSD1 (Fig. 5) [69].…”

Section: The 11␤-hydroxysteroid Dehydrogenase Type 1 (11␤-hsd1)mentioning

confidence: 99%

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The native anti-glucocorticoid paradigm

Hennebert

Morfin

2006

The Journal of Steroid Biochemistry and Molecular Biology

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“…Cytosolic malic enzyme is also increased by these hormones (70), and the response of these two enzymes to administered steroids thus provides a semiquantitative assay of activity. The two enzymes comprise a thermogenic system regulated by calcium and other factors (17,18,71,72).…”

Section: Dehydroepiandrosterone-a New Chaptermentioning

confidence: 99%

Happily at Work

Lardy

2003

Journal of Biological Chemistry

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It is a great privilege to be asked for a "Reflections" essay; I admire those prepared by my predecessors. My teachers were less prestigious than Arthur Kornberg's (1), and there was no single major theme in my research as was the case with several previous contributors to this series. Instead we studied a wide variety of metabolic phenomena that I have described in a summary of my first 50 years of biochemical research (2).Our findings included a treatment for selenium poisoning in livestock (undergraduate thesis; selenium-containing mercapturic acids are excreted in the urine) that was applied successfully to a human case; our studies of spermatozoa will be described in a following section. We elucidated the mechanism by which L-glyceraldehyde inhibits glycolysis (3). That disproved Needham's non-phosphorylating glycolysis in embryos and tumors. Could that have encouraged him to drop experiments and to devote his talents to prepare his magnificent history of Chinese science instead? We found that the function of biotin was to fix CO 2 in heterotrophic organisms (4); cellular respiration rates varied with the availability of inorganic P and phosphate acceptor (5, 6); propionate was metabolized by CO 2 addition to ultimately yield succinate (7,8). My students purified and crystallized some 10 phosphate-transferring enzymes, and we demonstrated that most of them required MgATP as substrate and were inhibited by free ATP; we found 16 different antibiotics that affected oxidative phosphorylation (9, 10) and a dozen that acted as ionophores (11), some of which are still being used in experiments. We also found that caffeine increased respiration and dramatically induced whiplash-type motility in sperm by increasing cyclic AMP (12, 13); the respiratory response was dependent on the utilization of acetylcarnitine (14). Thyroid hormone and also dehydroepiandrosterone induced the synthesis of mitochondrial glycerol-3-phosphate dehydrogenase to as much as 20 times the normal concentration (15-17) and formed part of a thermogenic system (17, 18). The path of carbon in gluconeogenesis was found to involve carboxylation of pyruvate (Utter reaction) in mitochondria, reduction of oxalacetate to malate, malate transport to cytosol in exchange for pyruvate, oxidation of malate to oxalacetate (the precursor of phosphopyruvate) together with the generation of the NADH required to reduce 3-phosphoglycerate to triose phosphate (19,20); serine was found to be converted to glucose by an entirely different pathway, probably the reverse of its synthesis from hydroxypyruvate (21). We also found that levels of liver cytosolic phosphoenolpyruvate carboxykinase (PEPCK) are regulated by the need for gluconeogenesis; they are increased by fasting and decreased in well fed animals; PEPCK is activated by ferrous ion, and in liver free calcium activates PEPCK by releasing Fe 2ϩ from mitochondria to the cytosol (22); feeding tryptophan inhibits gluconeogenesis because its metabolite, quinolinate, forms a complex with ferrous ion that blocks PEPC...

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Induction of Thermogenic Enzymes by DHEA and Its Metabolites

Cited by 28 publications

References 30 publications

7α- and 7β-hydroxy-epiandrosterone as substrates and inhibitors for the human 11β-hydroxysteroid dehydrogenase type 1

7α- and 7β-hydroxy-epiandrosterone as substrates and inhibitors for the human 11β-hydroxysteroid dehydrogenase type 1

The native anti-glucocorticoid paradigm

Happily at Work

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