Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes

Azzout‐Marniche, Dalila; Becard, Dominique; Guichard, C; Foretz, Marc; Ferré, Pascal; Foufelle, Fabienne

doi:10.1042/0264-6021:3500389

Cited by 147 publications

(168 citation statements)

References 15 publications

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“…The results are also consistent with the findings of Mauvoisin, et al (26), who showed that rapamycin blocks the induction of SCD-1, an SREBP-1c target gene, in chicken embryo hepatocytes. All of these results differ from the finding of Azzout-Marniche, et al (27), who failed to find an inhibitory effect of rapamycin on insulin-mediated increases in SREBP-1c mRNA and membrane-bound SREBP-1c protein in freshly isolated rat hepatocytes. In contrast with the current observation that rapamycin blocks SREBP-1c induction, we found that rapamycin failed to block the insulin-mediated repression of PEPCK in the same hepatocytes.…”

Section: Discussioncontrasting

confidence: 57%

Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis

Brown

Goldstein

2010

Proc. Natl. Acad. Sci. U.S.A.

632

538

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The livers of insulin-resistant, diabetic mice manifest selective insulin resistance, suggesting a bifurcation in the insulin signaling pathway: Insulin loses its ability to block glucose production (i.e., it fails to suppress PEPCK and other genes of gluconeogenesis), yet it retains its ability to stimulate fatty acid synthesis (i.e., continued enhancement of genes of lipogenesis). Enhanced lipogenesis is accompanied by an insulin-stimulated increase in the mRNA encoding SREBP-1c, a transcription factor that activates the entire lipogenic program. Here, we report a branch point in the insulin signaling pathway that may account for selective insulin resistance. Exposure of rat hepatocytes to insulin produced a 25-fold increase in SREBP-1c mRNA and a 95% decrease in PEPCK mRNA. Insulinmediated changes in both mRNAs were blocked by inhibitors of PI3K and Akt, indicating that these kinases are required for both pathways. In contrast, subnanomolar concentrations of rapamycin, an inhibitor of the mTORC1 kinase, blocked insulin induction of SREBP-1c, but had no effect on insulin suppression of PEPCK. We observed a similar selective effect of rapamycin in livers of rats and mice that experienced an insulin surge in response to a fastingrefeeding protocol. A specific inhibitor of S6 kinase, a downstream target of mTORC1, did not block insulin induction of SREBP-1c, suggesting a downstream pathway distinct from S6 kinase. These results establish mTORC1 as an essential component in the insulinregulated pathway for hepatic lipogenesis but not gluconeogenesis, and may help to resolve the paradox of selective insulin resistance in livers of diabetic rodents.Akt kinase | mTORC1 kinase | selective insulin resistance | SREBP-1c

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Section: Discussioncontrasting

confidence: 57%

Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis

Brown

Goldstein

2010

Proc. Natl. Acad. Sci. U.S.A.

632

538

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“…Nonetheless, whether similar regulation occurs centrally remains unknown. FAS is induced by both insulin and glucose in cell types such as the hepatocyte, while SREBP1c is induced by insulin only, with no significant change in SREBP1c mRNA in high glucose concentrations (25 mM) [2]. However, one study found that high glucose (25 mM) induces SREBP1c mRNA levels in the mouse hepatic cell line, H2-35 [7].…”

Section: Discussionmentioning

confidence: 96%

Fatty acid synthase gene regulation in primary hypothalamic neurons

Kim

Kleman

Ronnett

2007

Neuroscience Letters

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Understanding the mechanisms that regulate feeding is critical to the development of therapeutic interventions for obesity. Many studies indicate that enzymes within fatty acid metabolic pathways may serve as targets for pharmacological tools to treat this epidemic. We, and others have previously demonstrated that C75, a fatty acid synthase (FAS) inhibitor, induced significant anorexia and weight loss by both central and peripheral mechanisms. Because the hypothalamus is important in the regulation of homeostatic processes for feeding control, we have identified pathways that alter the gene expression of FAS in primary hypothalamic neuronal cultures. Insulin, glucose and AICAR (an activator of AMP-activated protein kinase) affected changes in hypothalamic FAS mRNA, which may be regulated via the SREBP1c dependent or independent pathway.

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“…Briefly, THP-1 cells were incubated for 24 h in RPMI 1640 with 300 nM PDB and 5% LPDS in the presence of the OSCi, 24(S),25-epoxy, 22(R)-OH, 25-OH, TO901317, or acetylated LDL. Total cell lysates were fractionated into postnuclear and nuclear fractions as described (29) and separated by SDS-PAGE (6% acrylamide for ABCA1 and 10% for SREBP-1). Proteins were transferred to polyvinylidene difluoride membranes and immunoblotted as described previously (19).…”

Section: Methodsmentioning

confidence: 99%

Selective Up-regulation of LXR-regulated Genes ABCA1, ABCG1, and APOE in Macrophages through Increased Endogenous Synthesis of 24(S),25-Epoxycholesterol

Beyea

Heslop

Sawyez

et al. 2007

Journal of Biological Chemistry

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Liver X receptor (LXR) activation represents a mechanism to prevent macrophage foam cell formation. Previously, we demonstrated that partial inhibition of oxidosqualene:lanosterol cyclase (OSC) stimulated synthesis of the LXR agonist 24(S),25-epoxycholesterol (24(S),25-epoxy) and enhanced ABCA1-mediated cholesterol efflux. In contrast to a synthetic, nonsteroidal LXR activator, TO-901317, triglyceride accumulation was not observed. In the present study, we determined whether endogenous 24(S),25-epoxy synthesis selectively enhanced expression of macrophage LXR-regulated cholesterol efflux genes but not genes that regulate fatty acid metabolism. THP-1 human macrophages incubated with the OSC inhibitor (OSCi) RO0714565 (15 nM) significantly reduced cholesterol synthesis and maximized synthesis of 24(S),25-epoxy. Endogenous 24(S),25-epoxy increased ABCA1, ABCG1, and APOE mRNA abundance and consequently increased cholesterol efflux to apoAI. In contrast, OSCi had no effect on LXR-regulated genes LPL (lipoprotein lipase) and FAS (fatty acid synthase). TO-901317 (>10 nM) significantly enhanced expression of all genes examined. OSCi and TO-901317 increased the mRNA and precursor form of SREBP1c, a major regulator of fatty acid and triglyceride synthesis. However, conversion of the precursor to the active form (nSREBP-1c) was blocked by OSCi-induced 24(S),25-epoxy but not by TO-901317 (>10 nM), which instead markedly increased nSREBP-1c. Disruption of nSREBP-1c formation by 24(S),25-epoxy accounted for diminished FAS and LPL expression. In summary, endogenous synthesis of 24(S),25-epoxy selectively up-regulates expression of macrophage LXR-regulated cholesterol efflux genes without stimulating genes linked to fatty acid and triglyceride synthesis.Macrophage-derived cholesteryl ester-rich foam cells develop within the arterial wall as a result of excessive internalization of lipoproteins, which subsequently promote early atherosclerotic plaque formation. In addition, foam cells enhance susceptibility to plaque rupture within advanced stage lesions, leading to further atherosclerosis complications (1, 2). The ligand-activated nuclear receptors known as liver X receptors (LXRs), 5 whose natural ligands are oxysterols, regulate the expression of genes involved in lipid homeostasis through binding to LXR response elements (LXREs) within the promoter of several responsive genes. These include ABCA1 (ATP-binding cassette A1), ABCG1, and APOE (apolipoprotein E), which mediate cellular cholesterol efflux from human and mouse macrophages to extracellular acceptors (3). Additionally, activated LXR increases expression of SREBP-1c (sterol regulatory element-binding protein 1c), FAS (fatty acid synthase), and LPL (lipoprotein lipase), which together act to stimulate cellular free fatty acid synthesis and free fatty acid uptake, respectively, leading to enhanced triglyceride synthesis (4 -6). SREBP-1c is itself a master regulator of genes involved in lipogenesis, such as LPL (7) and FAS (8), and is also self-regulating, since it posit...

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Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes

Cited by 147 publications

References 15 publications

Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis

Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis

Fatty acid synthase gene regulation in primary hypothalamic neurons

Selective Up-regulation of LXR-regulated Genes ABCA1, ABCG1, and APOE in Macrophages through Increased Endogenous Synthesis of 24(S),25-Epoxycholesterol

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