SIRT1 is a Highly Networked Protein That Mediates the Adaptation to Chronic Physiological Stress

Abstract

SIRT1 is a NAD + -dependent protein deacetylase that has a very large number of established protein substrates and an equally impressive list of biological functions thought to be regulated by its activity. Perhaps as notable is the remarkable number of points of conflict concerning the role of SIRT1 in biological processes. For example, evidence exists suggesting that SIRT1 is a tumor suppressor, is an oncogene, or has no effect on oncogenesis. Similarly, SIRT1 is variably reported to induce, inhibit, or have no effect on autophagy. We believe that the resolution of many conflicting results is possible by considering recent reports indicating that SIRT1 is an important hub interacting with a complex network of proteins that collectively regulate a wide variety of biological processes including cancer and autophagy. A number of the interacting proteins are themselves hubs that, like SIRT1, utilize intrinsically disordered regions for their promiscuous interactions. Many studies investigating SIRT1 function have been carried out on cell lines carrying undetermined numbers of alterations to the proteins comprising the SIRT1 network or on inbred mouse strains carrying fixed mutations affecting some of these proteins. Thus, the effects of modulating SIRT1 amount and/or activity are importantly determined by the genetic background of the cell (or the inbred strain of mice), and the effects attributed to SIRT1 are synthetic with the background of mutations and epigenetic differences between cells and organisms. Work on mice carrying alterations to the Sirt1 gene suggests that the network in which SIRT1 functions plays an important role in mediating physiological adaptation to various sources of chronic stress such as calorie restriction and calorie overload. Whether the catalytic activity of SIRT1 and the nuclear concentration of the co-factor, NAD + , are responsible for modulating this activity remains to be determined. However, the effect of modulating SIRT1 activity must be interpreted in the context of the cell or tissue under investigation. Indeed, for SIRT1, we argue that context is everything.

Resveratrol attenuates type 2 diabetes mellitus by mediating mitochondrial biogenesis and lipid metabolism via Sirtuin type 1

“…It has previously been demonstrated that RSV activates Sirtuin type 1 (SIRT1) to inhibit the development of T2DM (12). SIRT1 is a nuclear NAD + -dependent class III histone deacetylase that may regulate cell aging, life span and energy metabolism (13) by engaging in the reciprocal co-regulation of different binding partners (14). SIRT1 is able to adjust the deacetylase activity of various transcription factors that control metabolic and endocrine signals and is widely involved in regulating the mammalian cell life span, INS secretion and glucose/lipid metabolism (15).…”

<i>SIRT1</i> gene polymorphisms associated with carcass traits in Luxi cattle

“…Sirtuin 1, also known as NAD (nicotinamide adenine dinucleotide)-dependent deacetylase Sirtuin 1, is an NAD+-dependent protein deacetylase; it has many established protein substrates and is thought to regulate an impressive list of biological functions (McBurney et al, 2013). Sirtuin 1 has an important function in endocrine signaling, specifically in glucose and fat metabolism in mammals (Zillikens et al, 2009;.…”

The Role of Sirtuins in Cartilage Homeostasis and Osteoarthritis

“…The protective metabolic effects in mice treated with activators of SIRT1 are similar to those observed after treatment with resveratrol or SRT1720 [11,12]. Furthermore, restricting caloric intake promotes SIRT1 activity resulting in improved cell survival and metabolism and enhanced mitochondrial biogenesis through a myriad of pathways and networks [13]. Although not all sirtuins are equally affected by caloric intake as SIRT1, they are recognized as energy-sensing enzymes that function at various levels to fine-tune cellular metabolism.…”