Diverse roles of SIRT1 in cancer biology and lipid metabolism.

Glenn Simmons,Kevin Pruitt,Wendy Pruitt

doi:10.3390/ijms16010950

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.

Highlights

Mammalian sirtuins deacetylases consist of seven family members (SIRT1-7) that have been shown to be critical regulators of cell signaling pathways
There are likely many more components to the network of proteins involved in SIRT1-mediated lipid regulation, we have focused on a few select targets to demonstrate the breadth of SIRT1 regulation in lipid metabolism
SIRT1 potentiates the activity of Peroxisome Proliferator-Activated Receptor (PPAR)-α and PGC-1α, leading to increased lipolysis and fat loss in mature adipocytes [55]. This is important because activity of PGC-1α is critical to the activation of the SIRT1-dependent gluconeogenic pathway that is associated with the action of both Forkhead Box Protein O1 (FOXO1) and hepatocyte nuclear factor 4 α (HNF4-α) [56]

Summary

Introduction

Mammalian sirtuins deacetylases consist of seven family members (SIRT1-7) that have been shown to be critical regulators of cell signaling pathways. Because some members of the various classes of histone deacetylases (HDACs) have been shown to be overexpressed in diverse cancers, current views suggest that perturbed acetylation patterns on proteins may contribute to cellular transformation and tumor progression [2,3]. Influencing diverse physiological processes, it is not surprising that the role of SIRT1 in cellular growth control is complex and its enzymatic activity exerts important cell-type specific effects. This complexity, likewise, extends to studies involving human tumors. Due to the fact that SIRT1 activity regulates the function of signaling pathways associated with cell growth and motility [16,17,18], its overexpression could have grave consequences for tumor progression. We have highlighted reports on SIRT1-mediated regulation of processes involved in lipid metabolism and homeostasis and discuss the implications for tumor biology

Lipid Utilization in Tumor Cells

The Role of SIRT1 in Lipid Regulation

SIRT1 and Cholesterol Regulation

Findings

10. Conclusions