Diverse roles of SIRT1 in cancer biology and lipid metabolism

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.

Figure 1

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.