Effect of dexamethasone on gluconeogenesis, pyruvate kinase, pyruvate carboxylase and pyruvate dehydrogenase flux in isolated hepatocytes

Jones, Claire G.; Hothi, S K; Titheradge, Michael A.

doi:10.1042/bj2890821

Cited by 30 publications

(16 citation statements)

References 49 publications

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“…Glucocorticoids have been shown to acutely stimulate gluconeogenesis [198,199] and to result in an increased glucose output in rat hepatocytes [200]. It was suggested that glucocorticoids induce the gluconeogenic enzymes PC and PEPCK.…”

Section: Hormonal Alterationsmentioning

confidence: 99%

Structure, function and regulation of pyruvate carboxylase

Jitrapakdee

Wallace

1999

Biochemical Journal

183

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Pyruvate carboxylase (PC; EC 6.4.1.1), a member of the biotin-dependent enzyme family, catalyses the ATP-dependent carboxylation of pyruvate to oxaloacetate. PC has been found in a wide variety of prokaryotes and eukaryotes. In mammals, PC plays a crucial role in gluconeogenesis and lipogenesis, in the biosynthesis of neurotransmitter substances, and in glucose-induced insulin secretion by pancreatic islets. The reaction catalysed by PC and the physical properties of the enzyme have been studied extensively. Although no high-resolution three-dimensional structure has yet been determined by X-ray crystallography, structural studies of PC have been conducted by electron microscopy, by limited proteolysis, and by cloning and sequencing of genes and cDNA encoding the enzyme. Most well characterized forms of active PC consist of four identical subunits arranged in a tetrahedron-like structure. Each subunit contains three functional domains: the biotin carboxylation domain, the transcarboxylation domain and the biotin carboxyl carrier domain. Different physiological conditions, including diabetes, hyperthyroidism, genetic obesity and postnatal development, increase the level of PC expression through transcriptional and translational mechanisms, whereas insulin inhibits PC expression. Glucocorticoids, glucagon and catecholamines cause an increase in PC activity or in the rate of pyruvate carboxylation in the short term. Molecular defects of PC in humans have recently been associated with four point mutations within the structural region of the PC gene, namely Val145 → Ala, Arg451 → Cys, Ala610 → Thr and Met743 → Thr.

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Section: Hormonal Alterationsmentioning

confidence: 99%

Structure, function and regulation of pyruvate carboxylase

Jitrapakdee

Wallace

1999

Biochemical Journal

183

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“…Exposure to cortisol increases hepatic glucose output (Jones et al 1993) and adipocyte differentiation (Hauner et al 1987). Selective inhibitors have shown beneficial results in improving insulin sensitivity and causing weight loss (Alberts et al 2003, but the factors determining oxo-reductase activity per se have remained elusive.…”

Section: Introductionmentioning

confidence: 99%

Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11β-hydroxysteroid dehydrogenase type 1

Bujalska¹,

Draper²,

Michailidou³

et al. 2005

Journal of Molecular Endocrinology

149

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Two isozymes of 11 -hydroxysteroid dehydrogenase (11 -HSD) interconvert active cortisol and inactive cortisone. 11 -HSD2 (renal) acts only as a dehydrogenase, converting cortisol to cortisone. 11 -HSD1 (liver) is a bi-directional enzyme in cell homogenates, whereas in intact cells it typically displays oxo-reductase activity, generating cortisol from cortisone. We recently established that cortisone reductase deficiency is a digenic disease requiring mutations in both the gene encoding 11 -HSD1 and in the gene for a novel enzyme located within the lumen of the endoplasmic reticulum (ER), hexose-6-phosphate dehydrogenase (H6PDH). This latter enzyme generates NADPH, the co-factor required for oxo-reductase activity. Therefore, we hypothesized that H6PDH expression may be an important determinant of 11 -HSD1 oxo-reductase activity. Transient transfection of chinese hamster ovary (CHO) cells with 11 -HSD1 resulted in the appearance of both oxo-reductase and dehydrogenase activities in intact cells. Co-transfection of 11 -HSD1 with H6PDH increased oxo-reductase activity whilst virtually eliminating dehydrogenase activity. In contrast, H6PDH had no effect on reaction direction of 11 -HSD2, nor did the cytosolic enzyme, glucose-6-phosphate dehydrogenase (G6PD) affect 11 -HSD1 oxo-reductase activity. Conversely in HEK 293 cells stably transfected with 11 -HSD1 cDNA, transfection of an H6PDH siRNA reduced 11 -HSD1 oxo-reductase activity whilst simultaneously increasing 11 -HSD1 dehydrogenase activity. In human omental preadipocytes obtained from 15 females of variable body mass index (BMI), H6PDH mRNA levels positively correlated with 11 -HSD1 oxo-reductase activity, independent of 11 -HSD1 mRNA levels. H6PDH expression increased 5·3-fold across adipocyte differentiation (P,0·05) and was associated with a switch from 11 -HSD1 dehydrogenase to oxo-reductase activity. In conclusion, H6PDH is a crucial determinant of 11 -HSD1 oxo-reductase activity in intact cells. Through its interaction with 11 -HSD1, H6PDH may represent a novel target in the pathogenesis and treatment of obesity.

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“…Nonetheless, glucocorticoid pretreatment, using a dose comparable to the one used here, has been previously shown to maximize the gluconeogenic capacity of the liver via its ability to induce pyruvate carboxylase and phosphoenolpyruvate carboxykinase activity that is sustained over the ensuing 8-12 hr (16). This provided a counter-regulatory hormonal milieu similar to that which is present in the posttraumatic period (triple hormones) (15,17). Each liver was evaluated at a constant flow rate for a 2-hr period.…”

Section: Methodsmentioning

confidence: 99%

The Influence of Hepatic Venous Oxygen Saturation on the Liver's Synthetic Response to Metabolic Stress

Dahn

Lange²,

Benn³

1999

Proc Soc Exp Biol Med

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Hepatic oxygen consumption (HVO2) and hepatic venous oxygen saturation (ShvO2) were assessed in the isolated perfused rat liver under conditions that mimic critical illness in an effort to assess their utility in predicting the functional status of the liver. Flow rates were adjusted over the physiologic range of oxygen transport as indicated by the hepatic venous O2 saturation range of 10%-75%. HVO2 was found to be transport (HDO2) dependent only when perfusate conditions contained an increased counterregulatory hormone (glucagon, epinephrine, dexamethasone) stimulus or a high lactate concentration. In the absence of a metabolic load, (substrate and hormone-free perfusate), HVO2 was transport independent even at an ShvO2 as low as 10%. Although transport dependency of HVO2 is frequently used to infer tissue ischemia, hepatic oxygen consumption was poorly correlated with synthetic function under all conditions. In contrast, hepatic albumin production was directly related to ShvO2 at all levels of HDO2 and under all perfusion conditions indicating that this metabolic process is particularly sensitive to reductions in oxygen availability, which is more reliably predicted by venous saturation measurements. However, glucose and urea synthesis were almost independent of ShvO2. These findings indicate that various hepatic processes are affected differentially by stress conditions and flow alterations that may exist during critical illness, and protein synthesis is particularly sensitive to oxygen deprivation. Additionally, hepatic venous oxygen saturation measurement, but not HVO2, serves as a useful surrogate marker for hepatic albumin production suggesting that regional venous oximetry may play an important role in the detection of hepatic functional impairment.

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Effect of dexamethasone on gluconeogenesis, pyruvate kinase, pyruvate carboxylase and pyruvate dehydrogenase flux in isolated hepatocytes

Cited by 30 publications

References 49 publications

Structure, function and regulation of pyruvate carboxylase

Structure, function and regulation of pyruvate carboxylase

Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11β-hydroxysteroid dehydrogenase type 1

The Influence of Hepatic Venous Oxygen Saturation on the Liver's Synthetic Response to Metabolic Stress

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