The Akt–SREBP nexus: cell signaling meets lipid metabolism

Krycer, James R.; Sharpe, Laura J.; Luu, Winnie; Brown, Andrew

doi:10.1016/j.tem.2010.01.001

Cited by 307 publications

(258 citation statements)

References 68 publications

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“…Thus, the AR acts through multiple avenues to promote cholesterol accumulation in PCa (Fig. 8A), which in turn provides raw material for PCa cell growth and signaling (5).…”

Section: Discussionmentioning

confidence: 99%

Cross-talk between the Androgen Receptor and the Liver X Receptor

Krycer¹,

Brown

2011

Journal of Biological Chemistry

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High cholesterol levels are associated with prostate cancer development. Androgens promote cholesterol accumulation by activating the sterol-regulatory element-binding protein isoform 2 (SREBP-2) transcription factor. However, SREBP-2 is in balance with the liver X receptor (LXR; NR1H2/NR1H3), a transcription factor that prevents cholesterol accumulation. Here, we show that LXR activity is down-regulated by the androgen receptor (AR; NR3C4). In turn, this reduces LXR target gene expression. This antagonism on LXR is also exerted by other steroid hormone receptors, including the estrogen, glucocorticoid, and progesterone receptors. This suggests a generalizable mechanism, but the AR does not affect LXR mRNA levels, protein degradation, or DNA binding. We also found that the AR does not require protein synthesis to influence LXR, suggesting a direct antagonism. However, the AR does not directly bind LXR. The AR N-terminal domain (involved in transactivation), but not its DNA-binding domain, is required to suppress LXR activity, suggesting coactivator competition. Overall, this androgen-mediated antagonism of LXR complements SREBP-2 activation, providing a more complete picture as to how androgens increase cellular cholesterol levels in a prostate cancer setting. Given the cross-talk between other steroid hormone receptors and LXR, hormonal regulation of cholesterol via LXR may occur in a variety of cellular contexts.

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“…Thus, the AR acts through multiple avenues to promote cholesterol accumulation in PCa (Fig. 8A), which in turn provides raw material for PCa cell growth and signaling (5).…”

Section: Discussionmentioning

confidence: 99%

Cross-talk between the Androgen Receptor and the Liver X Receptor

Krycer¹,

Brown

2011

Journal of Biological Chemistry

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“…PI3K-Akt activation could lead to the increase of the protein levels of Sterol regulatory element-binding proteins (SREBP) as well as the gene expression of Fatty acid synthases (FAS) (Krycer et al, 2010;Jeon and Osborne, 2012). In addition, previous study has proposed a potential link between PI3K-Akt-mTOR pathway and fatty acid oxidation (Soliman, 2011).…”

Section: Introductionmentioning

confidence: 99%

Effects of inhibiting PI3K-Akt-mTOR pathway on lipid metabolism homeostasis in goose primary hepatocytes

Liu

Han

Wan

et al. 2016

Animal

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Phosphatidylinositol-3 kinases (PI3K)-Protein kinase B (Akt)-mammalian target of rapamycin (mTOR) pathway plays an important role in the synthesis and secretion of triacylglycerol. However, the mechanism of PI3K-Akt-mTOR pathway in regulating lipid metabolism of goose liver was poorly understood. The purpose of this study was to determine how PI3K-Akt-mTOR pathway regulating lipid metabolic homeostasis in goose hepatocytes. Goose primary hepatocytes were treated with different PI3K-Akt-mTOR signal inhibitors (LY294002, rapamycin and NVP-BEZ235) for 24 h. The results showed that these inhibitors evidently inhibited PI3K-Akt-mTOR downstream signaling. Meanwhile, these PI3K-Akt-mTOR inhibitors reduced intracellular lipid accumulation, decreased the mRNA expression and protein content of genes involved in the de novo fatty acid synthesis, while increased the transcriptional and protein level of key factors involved in fatty acid oxidation and very low density lipoprotein (VLDL) assembly and secretion. Conclusion: These findings suggested that the reduction of lipids accumulation induced-by inhibiting PI3K-Akt-mTOR pathway was closely linked to the decrease of lipogenesis, the increase of fatty acids oxidation, and the increase of VLDL assembly and secretion in goose hepatocytes.

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“…TORC1 enhances de novo lipogenesis by regulating the expression and processing of sterol regulatory element-binding protein 1c (SREBP1c) (Wan et al, 2011;Yecies et al, 2011), a master regulator of sterol and lipogenic gene transcription (Krycer et al, 2010). Furthermore, TORC1 increases glycolytic flux by activating the transcription and the translation of hypoxia inducible factor 1a (HIF1a) (Düvel et al, 2010), a positive regulator of many glycolytic genes (Gordan et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Postprandial regulation of hepatic glucokinase and lipogenesis requires the activation of TORC1 signaling in rainbow trout (Oncorhynchus mykiss)

Dai

Panserat

Mennigen

et al. 2013

Journal of Experimental Biology

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SUMMARYTo assess the potential involvement of TORC1 (target of rapamycin complex 1) signalling in the regulation of post-prandial hepatic lipid and glucose metabolism-related gene expression in trout, we employed intraperitoneal administration of rapamycin to achieve an acute inhibition of the TOR pathway. Our results reveal that rapamycin inhibits the phosphorylation of TORC1 and its downstream effectors (S6K1, S6 and 4E-BP1), without affecting Akt and the Akt substrates Forkhead-box Class O1 (FoxO1) and glycogen synthase kinase 3α/β (GSK 3α/β). These results indicate that acute administration of rapamycin in trout leads to the inhibition of TORC1 activation. No effect is observed on the expression of genes involved in gluconeogenesis, glycolysis and fatty acid oxidation, but hepatic TORC1 inhibition results in decreased sterol regulatory element binding protein 1c (SREBP1c) gene expression and suppressed fatty acid synthase (FAS) and glucokinase (GK) at gene expression and activity levels, indicating that FAS and GK activity is controlled at a transcriptional level in a TORC1-dependent manner. This study demonstrates for the first time in fish that post-prandial regulation of hepatic lipogenesis and glucokinase in rainbow trout requires the activation of TORC1 signalling.

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The Akt–SREBP nexus: cell signaling meets lipid metabolism

Cited by 307 publications

References 68 publications

Cross-talk between the Androgen Receptor and the Liver X Receptor

Cross-talk between the Androgen Receptor and the Liver X Receptor

Effects of inhibiting PI3K-Akt-mTOR pathway on lipid metabolism homeostasis in goose primary hepatocytes

Postprandial regulation of hepatic glucokinase and lipogenesis requires the activation of TORC1 signaling in rainbow trout (Oncorhynchus mykiss)

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