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Diverse roles of SIRT1 in cancer biology and lipid metabolism.

Simmons GE, Pruitt WM, Pruitt K - Int J Mol Sci (2015)

Bottom Line: Not only does SIRT1 have the potential to regulate oncogenic factors, it also orchestrates many aspects of metabolism and lipid regulation and recent reports are beginning to connect these areas.SIRT1 influences pathways that provide an alternative means of deriving energy (such as fatty acid oxidation and gluconeogenesis) when a cell encounters nutritive stress, and can therefore lead to altered lipid metabolism in various pathophysiological contexts.This review helps to show the various connections between SIRT1 and major pathways in cellular metabolism and the consequence of SIRT1 deregulation on carcinogenesis and lipid metabolism.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. glenn.simmons@utsouthwestern.edu.

ABSTRACT
SIRT1, an NAD(+)-dependent deacetylase, has been described in the literature as a major player in the regulation of cellular stress responses. Its expression has been shown to be altered in cancer cells, and it targets both histone and non-histone proteins for deacetylation and thereby alters metabolic programs in response to diverse physiological stress. Interestingly, many of the metabolic pathways that are influenced by SIRT1 are also altered in tumor development. Not only does SIRT1 have the potential to regulate oncogenic factors, it also orchestrates many aspects of metabolism and lipid regulation and recent reports are beginning to connect these areas. SIRT1 influences pathways that provide an alternative means of deriving energy (such as fatty acid oxidation and gluconeogenesis) when a cell encounters nutritive stress, and can therefore lead to altered lipid metabolism in various pathophysiological contexts. This review helps to show the various connections between SIRT1 and major pathways in cellular metabolism and the consequence of SIRT1 deregulation on carcinogenesis and lipid metabolism.

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Key lipid regulatory pathways influenced by SIRT1 deacetylase activity. The crosstalk between various signaling pathways allows for SIRT1 activity to function as a potent regulator of lipid homeostasis. Depicted, SIRT1 activation in response to extracellular stimuli, such as caloric restriction or pharmacologic agonist, can lead to the activation of many proteins which have been demonstrated to abrogate lipogenesis by inhibiting master lipid regulator sterol regulatory element-binding protein (SREBP1), while enhancing fat mobilization in cells.
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ijms-16-00950-f001: Key lipid regulatory pathways influenced by SIRT1 deacetylase activity. The crosstalk between various signaling pathways allows for SIRT1 activity to function as a potent regulator of lipid homeostasis. Depicted, SIRT1 activation in response to extracellular stimuli, such as caloric restriction or pharmacologic agonist, can lead to the activation of many proteins which have been demonstrated to abrogate lipogenesis by inhibiting master lipid regulator sterol regulatory element-binding protein (SREBP1), while enhancing fat mobilization in cells.

Mentions: SIRT1 does not only influence nuclear factors, there are also considerable interactions with upstream enzymes that regulate the activity of key cellular pathways. AMP-activated protein kinase (AMPK), for instance is an energy sensor in the cell and is activated upon increases in the AMP/ATP ratio. AMPK is directly activated by phosphorylation carried out by upstream kinases: Calmodulin-dependent kinase kinase β (CamKK), transforming growth factor-activated kinase-1 (TAK1), or by tumor suppressor liver kinase β-1 (LKB1) [35]. However, acetylation of LKB1 at specific lysine residues (K48) regulates kinase activity and the activity of its protein substrates. Deacetylation of LKB1 by SIRT1 potentiates the activity of LKB1 targets such as AMPK. Subsequently, AMPK activity inhibited acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) and thus limits the generation of fatty acids [60] (Figure 1). SIRT1 by virtue of its interaction with the LKB1 blocks the synthesis of lipids via the de novo synthesis pathway.


Diverse roles of SIRT1 in cancer biology and lipid metabolism.

Simmons GE, Pruitt WM, Pruitt K - Int J Mol Sci (2015)

Key lipid regulatory pathways influenced by SIRT1 deacetylase activity. The crosstalk between various signaling pathways allows for SIRT1 activity to function as a potent regulator of lipid homeostasis. Depicted, SIRT1 activation in response to extracellular stimuli, such as caloric restriction or pharmacologic agonist, can lead to the activation of many proteins which have been demonstrated to abrogate lipogenesis by inhibiting master lipid regulator sterol regulatory element-binding protein (SREBP1), while enhancing fat mobilization in cells.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4307284&req=5

ijms-16-00950-f001: Key lipid regulatory pathways influenced by SIRT1 deacetylase activity. The crosstalk between various signaling pathways allows for SIRT1 activity to function as a potent regulator of lipid homeostasis. Depicted, SIRT1 activation in response to extracellular stimuli, such as caloric restriction or pharmacologic agonist, can lead to the activation of many proteins which have been demonstrated to abrogate lipogenesis by inhibiting master lipid regulator sterol regulatory element-binding protein (SREBP1), while enhancing fat mobilization in cells.
Mentions: SIRT1 does not only influence nuclear factors, there are also considerable interactions with upstream enzymes that regulate the activity of key cellular pathways. AMP-activated protein kinase (AMPK), for instance is an energy sensor in the cell and is activated upon increases in the AMP/ATP ratio. AMPK is directly activated by phosphorylation carried out by upstream kinases: Calmodulin-dependent kinase kinase β (CamKK), transforming growth factor-activated kinase-1 (TAK1), or by tumor suppressor liver kinase β-1 (LKB1) [35]. However, acetylation of LKB1 at specific lysine residues (K48) regulates kinase activity and the activity of its protein substrates. Deacetylation of LKB1 by SIRT1 potentiates the activity of LKB1 targets such as AMPK. Subsequently, AMPK activity inhibited acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) and thus limits the generation of fatty acids [60] (Figure 1). SIRT1 by virtue of its interaction with the LKB1 blocks the synthesis of lipids via the de novo synthesis pathway.

Bottom Line: Not only does SIRT1 have the potential to regulate oncogenic factors, it also orchestrates many aspects of metabolism and lipid regulation and recent reports are beginning to connect these areas.SIRT1 influences pathways that provide an alternative means of deriving energy (such as fatty acid oxidation and gluconeogenesis) when a cell encounters nutritive stress, and can therefore lead to altered lipid metabolism in various pathophysiological contexts.This review helps to show the various connections between SIRT1 and major pathways in cellular metabolism and the consequence of SIRT1 deregulation on carcinogenesis and lipid metabolism.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. glenn.simmons@utsouthwestern.edu.

ABSTRACT
SIRT1, an NAD(+)-dependent deacetylase, has been described in the literature as a major player in the regulation of cellular stress responses. Its expression has been shown to be altered in cancer cells, and it targets both histone and non-histone proteins for deacetylation and thereby alters metabolic programs in response to diverse physiological stress. Interestingly, many of the metabolic pathways that are influenced by SIRT1 are also altered in tumor development. Not only does SIRT1 have the potential to regulate oncogenic factors, it also orchestrates many aspects of metabolism and lipid regulation and recent reports are beginning to connect these areas. SIRT1 influences pathways that provide an alternative means of deriving energy (such as fatty acid oxidation and gluconeogenesis) when a cell encounters nutritive stress, and can therefore lead to altered lipid metabolism in various pathophysiological contexts. This review helps to show the various connections between SIRT1 and major pathways in cellular metabolism and the consequence of SIRT1 deregulation on carcinogenesis and lipid metabolism.

Show MeSH
Related in: MedlinePlus