The synergistic effect of cortisone and insulin on lipogenesis in the perfused rat liver as studied with α-C14-acetate

Altman, Kurt I.; Miller, Leon L.; Bly, C. G.

doi:10.1016/0003-9861(51)90225-1

Cited by 27 publications

(8 citation statements)

References 11 publications

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“…Liver triglyceride levels were significantly increased with DEX in all genotypes except Lxrβ -/-, although the same trend was observed in this genotype ( Figure 5D). These data correlate strongly with the insulin levels measured after DEX treatment (Figure 5B), supporting the essential role of insulin in the development of GC-induced hepatic steatosis (52,53).…”

Section: Lxrα/β -/-Mice Differentially Activate Gr Target Genes In LIsupporting

confidence: 74%

“…In fact, GCs alone, in the absence of insulin, do not promote fatty acid synthesis (53). However, when combined with insulin, GCs synergistically increase de novo lipogenesis (52). While extensive studies have been performed to understand the molecular regulation of gluconeogenesis by GCs (61), the detailed molecular mechanisms by which GCs induce fatty liver have not been well characterized (9).…”

Section: Discussionmentioning

confidence: 99%

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LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice

Patel¹,

Patel²,

Tsai³

et al. 2011

J. Clin. Invest.

108

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Although widely prescribed for their potent antiinflammatory actions, glucocorticoid drugs (e.g., dexamethasone) cause undesirable side effects that are features of the metabolic syndrome, including hyperglycemia, fatty liver, insulin resistance, and type II diabetes. Liver x receptors (LXRs) are nuclear receptors that respond to cholesterol metabolites and regulate the expression of a subset of glucocorticoid target genes. Here, we show LXRβ is required to mediate many of the negative side effects of glucocorticoids. Mice lacking LXRβ (but not LXRα) were resistant to dexamethasone-induced hyperglycemia, hyperinsulinemia, and hepatic steatosis, but remained sensitive to dexamethasone-dependent repression of the immune system. In vivo, LXRα/β knockout mice demonstrated reduced dexamethasone-induced expression of the key hepatic gluconeogenic gene, phosphoenolpyruvate carboxykinase (PEPCK). In perfused liver and primary mouse hepatocytes, LXRβ was required for glucocorticoid-induced recruitment of the glucocorticoid receptor to the PEPCK promoter. These findings suggest a new avenue for the design of safer glucocorticoid drugs through a mechanism of selective glucocorticoid receptor transactivation.

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Section: Lxrα/β -/-Mice Differentially Activate Gr Target Genes In LIsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice

Patel¹,

Patel²,

Tsai³

et al. 2011

J. Clin. Invest.

108

View full text Add to dashboard Cite

show abstract

“…Nonalcoholic fatty liver can be a result of excessive lipogenesis, decreased fatty acid oxidation, decreased secretion of VLDL particles, or a combination of more than one causes. It has been reported that GCs contribute to hepatosteatosis through a combination of increased fatty acid synthesis and decreased fatty acid βoxidation (40, 41). In our study, administration of Dex at 15mg/kg significantly increases hepatic TG content and expression of lipogenic genes.…”

Section: Discussionmentioning

confidence: 99%

FOXO1-dependent up-regulation of MAP kinase phosphatase 3 (MKP-3) mediates glucocorticoid-induced hepatic lipid accumulation in mice

Feng

2014

Molecular and Cellular Endocrinology

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Long-term treatment with glucocorticoids (GCs) or dysregulation of endogenous GC levels induces a series of metabolic diseases, such as insulin resistance, obesity and type 2 diabetes. We previously showed that MAP kinase phosphatase-3 (MKP-3) plays an important role in glucose metabolism. The aim of this study is to investigate the role of MKP-3 in GC-induced metabolic disorders. Dexamethasone (Dex), a synthetic GC, increases MKP-3 protein expression both in cultured hepatoma cells and in the liver of lean mice. This effect is likely mediated by forkhead box protein O1 (FOXO1) because disruption of endogenous FOXO1 function by either interfering RNA mediated FOXO1 knockdown or overexpression of a dominant negative FOXO1 mutant blocks Dex-induced upregulation of MKP-3 protein. In addition, overexpression of FOXO1 is sufficient to induce MKP-3 protein expression. MKP-3 deficient mice are protected from several side effects of chronic Dex exposure, such as body weight gain, adipose tissue enlargement, hepatic lipid accumulation, and insulin resistance. The beneficial phenotypes in mice lacking MKP-3 are largely attributed to the absence of MKP-3 in the liver since only hepatic insulin signaling has been preserved among the three insulin target tissues (liver, muscle and adipose tissue).

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“…This effect of glucocorticoids was first demonstrated by Altman et al (1951), who showed that pharmacological amounts of insulin and glucocorticoids act synergistically to enhance lipogenesis in the perfused liver. Subsequent studies indicated that the administration of glucocorticoids to rats increases the activity of hepatic acetyl-CoA carboxylase and fatty acid synthetase as well as lipogenesis from [1-'4C]acetyl-CoA (Diamant & Shafrir, 1975).…”

Section: Discussionmentioning

confidence: 99%

“…The role of glucocorticoids in the regulation of hepatic lipogenic enzymes and lipogenesis has been .studied in intact animals and in the perfused rat liver (Altman et al, 1951;Diamant & Shafrir, 1975;Kirk et al, 1976). This effect of glucocorticoids was first demonstrated by Altman et al (1951), who showed that pharmacological amounts of insulin and glucocorticoids act synergistically to enhance lipogenesis in the perfused liver.…”

Section: Discussionmentioning

confidence: 99%

The effects of glucocorticoids on insulin-stimulated lipogenesis in primary cultures of rat hepatocytes

Amatruda¹,

Danahy²,

Chang³

1983

Biochemical Journal

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We used primary cultures of rat hepatocytes to evaluate the effects of glucocorticoids on insulin-responsive hepatic lipogenesis. The data indicate that hepatocytes incubated for 20 h with dexamethasone (0.1 M) alone are profoundly resistant to the ability of insulin to stimulate lipogenesis acutely. In contrast, primary cultures of hepatocytes incubated with dexamethasone plus insulin are hyper-responsive to the ability of insulin to stimulate lipogenesis chronically. This potentiation of insulin action by a glucocorticoid occurs at physiological concentrations of the two hormones. Exposure to dexamethasone plus insulin for more than 4h is required for the two hormones to enhance insulin action either by overcoming the insulin resistance induced by dexamethasone alone or by stimulating insulin action induced by insulin alone. Despite the marked potentiation of insulin action, hepatocytes exposed to dexamethasone plus insulin are less sensitive to insulin, as demonstrated by a shift to the right in the dose-response curve for insulin-stimulated lipogenesis. The resistance of hepatocytes to the acute effects of insulin after exposure to dexamethasone alone and the potentiation of insulin action and decreased sensitivity to insulin after exposure to insulin plus dexamethasone are all mediated by post-insulin-binding events. These studies demonstrate potentiation of insulin action in the liver by physiological concentrations of glucocorticoids and may have physiological significance for the regulation of normal hepatic lipogenesis, for the hyperlipidaemia observed with the pharmacological use of glucocorticoids, and for disease states in man associated with hyperinsulinaemia and hypercortisolism.

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The synergistic effect of cortisone and insulin on lipogenesis in the perfused rat liver as studied with α-C14-acetate

Cited by 27 publications

References 11 publications

LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice

LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice

FOXO1-dependent up-regulation of MAP kinase phosphatase 3 (MKP-3) mediates glucocorticoid-induced hepatic lipid accumulation in mice

The effects of glucocorticoids on insulin-stimulated lipogenesis in primary cultures of rat hepatocytes

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