Dehydroepiandrosterone reduces expression of glycolytic and gluconeogenic enzymes in the liver of male and female rats

Mayer, Doris; Reuter, Stephan; Hoffmann, Hanne M.; Bocker, Thomas; Bannasch, P

doi:10.3892/ijo.8.6.1069

Cited by 6 publications

(4 citation statements)

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“…Table 1 summarizes the lobular distribution of glycogen content and enzyme activities determined by histochemistry in normal liver, and the alterations in the intensity of reactions and in lobular distribution induced by DHEA-treatment. Quantitative studies on enzyme activities in liver homogenates confirmed these results and showed that females were more affected than males (20). mRNA analysis indicated that the change in enzyme activity was associated with altered transcriptional expression.…”

Section: Alterations In Energy Metabolism Of Rat Liver Induced By Dheamentioning

confidence: 58%

“…Administration of DHEA to rats results in significant alterations in energy metabolism of the liver which have been reviewed in detail previously (2,3,16,17,19). Besides a decrease in glycogen and lipid contents, changes of the activity of key enzymes of glucose and lipid metabolism were observed that point to an overall energy expenditure in liver (18,20,21). Table 1 summarizes the lobular distribution of glycogen content and enzyme activities determined by histochemistry in normal liver, and the alterations in the intensity of reactions and in lobular distribution induced by DHEA-treatment.…”

Section: Alterations In Energy Metabolism Of Rat Liver Induced By Dheamentioning

confidence: 99%

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Induction and Modulation of Hepatic Preneoplasia and Neoplasia in the Rat by Dehydroepiandrosterone

Mayer

Kopplow

2003

Toxicol Pathol

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Dehydroepiandrosterone (DHEA), the main adrenal steroid in humans and a precursor in androgen and estrogen biosynthesis, acts as a peroxisome proliferator and as a hepatocarcinogen in rats. Neoplasms emerge from a glycogenotic/amphophilic/basophilic preneoplastic cell lineage. A higher female tumor incidence suggests a relevant influence of sex hormones. DHEA enhances hepatocarcinogenesis induced by N-nitrosomorpholine (NNM), which is characterized by the glycogenotic/basophilic cell lineage. The tumor promoting effect is related to an additional amphophilic/basophilic preneoplastic lesion sequence and to faster proliferation of the basophilic preneoplastic lesions. Nevertheless, hepatocellular carcinomas provided under DHEA treatment seem to have a less malignant phenotype compared to tumors induced by NNM only. Further, DHEA treatment reduces growth and generation of glycogen storage foci (GSF) in initial NNM-treated rats. Thus, DHEA treatment results in both, a growth stimulation of the late basophilic lesion type with an additional amphophilic lesion sequence, and in a growth inhibition of early preneoplastic lesions, addressing especially GSF. DHEA also inhibits the growth of physiologically proliferating liver tissue. This might be explained by a DHEA related cellular metabolism, which results in significant energy consumption. Additionally, a DHEA-induced alteration of cytokine levels might contribute to this growth inhibition as well.

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Section: Alterations In Energy Metabolism Of Rat Liver Induced By Dheamentioning

confidence: 58%

Section: Alterations In Energy Metabolism Of Rat Liver Induced By Dheamentioning

confidence: 99%

Induction and Modulation of Hepatic Preneoplasia and Neoplasia in the Rat by Dehydroepiandrosterone

Mayer

Kopplow

2003

Toxicol Pathol

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“…It is well known that fat accumulation relies on excess energy supply in the body. It was reported that DHEA treatment significantly promoted glucose conversion to glycogen, which could be one of the mechanisms controlling serum glucose levels [ 35 ]. Our results indicated that no differences were observed in glucose levels, whereas hepatic glycogen contents were markedly higher in the 50 and 100 mg·kg −1 DHEA treatment groups, and muscle glycogen contents were dramatically higher in the 25 and 50 mg·kg −1 DHEA treatment groups.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Administration of Dehydroepiandrosterone Accelerates Glucose Catabolism via Activation of PI3K/Akt-PFK-2 Signaling Pathway in Rats Fed a High-Fat Diet

Kang

et al. 2016

PLoS ONE

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Dehydroepiandrosterone (DHEA) has a fat-reducing effect, while little information is available on whether DHEA regulates glucose metabolism, which would in turn affect fat deposition. To investigate the effects of DHEA on glucose metabolism, rats were administered a high-fat diet containing either 0 (HCG), 25 (HLG), 50 (HMG), or 100 (HHG) mg·kg-1 DHEA per day via gavage for 8 weeks. Results showed that long-term administration of DHEA inhibited body weight gain in rats on a high-fat diet. No statistical differences in serum glucose levels were observed, whereas hepatic glycogen content in HMG and HHG groups and muscle glycogen content in HLG and HMG groups were higher than those in HCG group. Glucokinase, malate dehydrogenase and phosphofructokinase-2 activities in HMG and HHG groups, pyruvate kinase and succinate dehydrogenase activities in HMG group, and pyruvate dehydrogenase activity in all DHEA treatment groups were increased compared with those in HCG group. Phosphoenolpyruvate carboxykinase and glycogen phosphorylase mRNA levels were decreased in HMG and HHG groups, whereas glycogen synthase-2 mRNA level was increased in HMG group compared with those in HCG. The abundance of Glut2 mRNA in HMG and HHG groups and Glut4 mRNA in HMG group was higher than that in HCG group. DHEA treatment increased serum leptin content in HMG and HHG groups compared with that in HCG group. Serum insulin content and insulin receptor mRNA level in HMG group and insulin receptor substrate-2 mRNA level in HMG and HHG group were increased compared with those in HCG group. Furthermore, Pi3k mRNA level in HMG and Akt mRNA level in HMG and HHG groups were significantly increased than those in HCG group. These data showed that DHEA treatment could enhance glycogen storage and accelerate glucose catabolism in rats fed a high-fat diet, and this effect may be associated with the activation of PI3K/Akt-PFK-2 signaling pathway.

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“…P53 also regulates HK activity by enhancing the maturation of miR-143, a potent inhibitor of HK expression. 27,28 In cells in which p53 has been inactivated, G6P levels will rise because of loss of miR-143 regulation of HK, and most or all G6PD enzymes will consequently be sequestered within an E-S complex sensitive to uncompetitive inhibition by DHEA. The kill-switch mechanism that we propose depends upon simultaneous rapid upregulation of DHEA concentrations upon p53 inactivation in a cell.…”

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confidence: 99%

Species specificity of an adrenal androgen-mediated kill-switch triggered by p53 inactivation

Nyce¹

2017

Transl Med Rep

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Glucose-6-phosphate dehydrogenase (G6PD) is an oncoprotein that is regulated by the p53 tumor suppressor. Mutant p53 loses the ability to inhibit G6PD, and loss of G6PD control clearly plays a role in oncogenesis. The steroid hormone precursor dehydroepiandrosterone (DHEA) is an endogenous uncompetitive inhibitor of G6PD. In humans, and a few other species, the sulfated circulatory form of DHEA (DHEAS) is present at extremely high concentrations -much higher than can be accounted for by DHEA's function as a precursor to steroid hormones. Uncompetitive inhibition is extremely rare in natural systems because it is irreversible in the presence of high concentrations of substrate and inhibitor. What has gone unappreciated is that such uncompetitive inhibition can quickly lead to cell death when the target is an obligatory housekeeping gene such as G6PD. Cells with inactivated p53 not only lose control over G6PD, but also over hexokinase (HK), the enzyme that converts glucose into glucose-6-phosphate (G6P), the substrate of G6PD. Furthermore, loss of p53 function de-represses NFκB activity, resulting in the upregulation of steroid sulfatase (SS) which converts circulating DHEAS into active DHEA. We propose that inactivation of p53 rapidly elevates G6P and DHEA concentrations in affected cells, driving uncompetitive inhibition of G6PD to lethal irreversibility. In animals with circulating DHEAS, this kill-switch mechanism may prevent most cases of p53 inactivation from becoming tumorigenic. Tumors would thus represent instances in which this mechanism had not been triggered, but which might still be triggered by application of DHEA sufficient to uncompetitively inhibit tumor G6PD. To test this hypothesis, we performed a pilot study in which dogs with cardiac hemangiosarcoma were treated with high dose (HD) DHEA supplemented with isoprene precursors to maintain geranylation of Rac GTPase. Tumor regression and longevity observed in these dogs supported the concept that some tumors retain extraordinary sensitivity to uncompetitive inhibition by DHEA.

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Dehydroepiandrosterone reduces expression of glycolytic and gluconeogenic enzymes in the liver of male and female rats

Cited by 6 publications

References 0 publications

Induction and Modulation of Hepatic Preneoplasia and Neoplasia in the Rat by Dehydroepiandrosterone

Induction and Modulation of Hepatic Preneoplasia and Neoplasia in the Rat by Dehydroepiandrosterone

Long-Term Administration of Dehydroepiandrosterone Accelerates Glucose Catabolism via Activation of PI3K/Akt-PFK-2 Signaling Pathway in Rats Fed a High-Fat Diet

Species specificity of an adrenal androgen-mediated kill-switch triggered by p53 inactivation

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