PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP

Porstmann, T; Griffiths, Beatrice; Chung, Yuen‐Li; Delpuech, Oona; Griffiths, John R.; Downward, Julian; Schulze, Almut

doi:10.1038/sj.onc.1208802

Cited by 399 publications

(334 citation statements)

References 76 publications

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“…Lithium did not significantly inhibit ethanol-induced accumulation of TG and ceramide. While activation of AMPK inhibits lipogenesis in peripheral tissues [36], activation of Akt enhances lipogenesis [37]. Further studies on the activities and subcellular localization of AMPK and Akt may give insight into the roles of these protein kinases particularly during neurodegeneration of the developing brain by ethanol and the neuroprotective action of lithium.…”

Section: Discussionmentioning

confidence: 99%

Lithium blocks ethanol-induced modulation of protein kinases in the developing brain

Chakraborty

Shimada

Mao

et al. 2008

Biochemical and Biophysical Research Communications

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Lithium has been shown to be neuroprotective against various insults including ethanol exposure. We previously reported that ethanol-induced apoptotic neurodegeneration in the postnatal day 7 (P7) mice is associated with decreases in phosphorylation levels of Akt, glycogen synthase kinase-3β (GSK-3β), and AMP-activated protein kinase (AMPK), and alteration in lipid profiles in the brain. Here, P7 mice were injected with ethanol and lithium, and the effects of lithium on ethanol-induced alterations in phosphorylation levels of protein kinases and lipid profiles in the brain were examined. Immunoblot and immunohistochemical analyses showed that lithium significantly blocked ethanolinduced caspase-3 activation and reduction in phosphorylation levels of Akt, GSK-3β and AMPK. Further, lithium inhibited accumulation of cholesterol ester (ChE) and Nacylphosphatidylethanolamine (NAPE) triggered by ethanol in the brain. These results suggest that Akt, GSK-3β, and AMPK are involved in ethanol-induced neurodegeneration and the neuroprotective effects of lithium by modulating both apoptotic and survival pathways.

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Section: Discussionmentioning

confidence: 99%

Lithium blocks ethanol-induced modulation of protein kinases in the developing brain

Chakraborty

Shimada

Mao

et al. 2008

Biochemical and Biophysical Research Communications

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“…However, mammary-specific over-expression of a constituently active Akt1 more than doubled the milk fat concentration (Schwertfeger et al, Milk fat depression 2003). Activation of Akt1 increases lipid synthesis through modification of multiple levels of SREBP1 regulation (Porstmann et al, 2005). First, Akt1 promotes processing of SREBP1, increasing nSREBP1 synthesis (Porstmann et al, 2005;Du et al, 2006).…”

Section: Sterol Response Element-binding Protein-1mentioning

confidence: 99%

“…Activation of Akt1 increases lipid synthesis through modification of multiple levels of SREBP1 regulation (Porstmann et al, 2005). First, Akt1 promotes processing of SREBP1, increasing nSREBP1 synthesis (Porstmann et al, 2005;Du et al, 2006). Secondly, nSREBP1 is targeted to proteosomal degradation by GSK3b-dependent phosphorylation, and Akt1 may increase nSREBP1 abundance by inactivating GSK3b (Rudolph et al, 2007;Jump et al, 2008).…”

Section: Sterol Response Element-binding Protein-1mentioning

confidence: 99%

Recent advances in the regulation of milk fat synthesis

Harvatine

Boisclair

Bauman

2009

Animal

268

272

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In addition to its economic value, milk fat is responsible for many of milk's characteristics and can be markedly affected by diet. Diet-induced milk fat depression (MFD) was first described over a century ago and remains a common problem observed under both intensive and extensive management. The biohydrogenation theory established that MFD is caused by an inhibition of mammary synthesis of milk fat by specific fatty acids (FA) produced as intermediates in ruminal biohydrogenation. During MFD, lipogenic capacity and transcription of key lipid synthesis genes in the mammary gland are down-regulated in a coordinated manner. Our investigations have established that expressions of sterol response element-binding protein 1 (SREBP1) and SREBP-activation proteins are down-regulated during MFD. Importantly, key lipogenic enzymes are transcriptionally regulated via SREBP1. Collectively, these results provide strong evidence for SREBP1 as a central signaling pathway in the regulation of mammary FA synthesis. Spot 14 is also down-regulated during MFD, consistent with a lipogenic role for this novel nuclear protein. In addition, SREBP1c and Spot 14 knock-out mice exhibit reduced milk fat similar to the magnitude and pattern of MFD in the cow. Application of molecular biology approaches has provided the latest chapter in the regulation of milk fat synthesis and is reviewed along with a brief background in nutritional regulation of milk fat synthesis in ruminants.

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“…1A shows a simplified representation of the kinase cascades activated by insulin in mammalian liver, highlighting the pathways that are felt to activate transcription of SREBP-1c (lipogenesis) or inhibit transcription of PEPCK (gluconeogenesis). Previous reports suggest that insulin-mediated stimulation of SREBP-1c expression is dependent on PI3K (15)(16)(17)20). The downstream pathway by which PI3K regulates SREBP-1c transcription in liver remains unclear.…”

mentioning

confidence: 98%

“…1A). Inhibitor studies in cultured cells, and gene knockout experiments in mice, have shown that this pathway is required both for inhibition of FoxO1 activity (13,14) and for induction of SREBP-1c expression (15)(16)(17). Therefore, it is likely that the bifurcation must occur distal to Akt.…”

mentioning

confidence: 99%

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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PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP

Cited by 399 publications

References 76 publications

Lithium blocks ethanol-induced modulation of protein kinases in the developing brain

Lithium blocks ethanol-induced modulation of protein kinases in the developing brain

Recent advances in the regulation of milk fat synthesis

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

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