SIRT1 and other sirtuins in metabolism

Abstract

Sirtuins such as SIRT1 are conserved protein NAD(+)-dependent deacylases and thus their function is intrinsically linked to cellular metabolism. Over the past two decades, accumulating evidence has indicated that sirtuins are not only important energy status sensors but also protect cells against metabolic stresses. Sirtuins regulate the aging process and are themselves regulated by diet and environmental stress. The versatile functions of sirtuins including, more specifically, SIRT1 are supported by their diverse cellular location allowing cells to sense changes in energy levels in the nucleus, cytoplasm, and mitochondrion. SIRT1 plays a critical role in metabolic health by deacetylating many target proteins in numerous tissues, including liver, muscle, adipose tissue, heart, and endothelium. This sirtuin also exerts important systemic effects via the hypothalamus. This review will cover these topics and suggest that strategies to maintain sirtuin activity may be on the horizon to forestall diseases of aging.

Keywords: CR mimetics; NAD(+); SIRT1; aging; calorie restriction; metabolism; sirtuins.

Figure 1. SIRT1 mediates metabolic benefits in various tissues

Major metabolic tissues, such as liver, heart, white adipose tissue (WAT) and skeletal muscle are depicted to illustrate SIRT1 functions. In the liver, SIRT1 supports gluconeogenesis via PGC-1α and FOXO1[57], and facilitates CRCT2 degradation upon prolonged fasting [56]. SIRT1 inhibits glycolysis by repressing glycolytic enzyme PGAM-1 [59]. In the liver, SIRT1 responds to fasting and promotes fatty acid oxidation by activating PPARα [58] and inhibits fatty acid synthesis by targeting SREBP1c for degradation [63]. SIRT1 is a positive regulator of LXR and thus regulates whole-body cholesterol homeostasis [64]. In the skeletal muscle, SIRT1 exerts similar actions on increasing fatty acid utilization, and reduces glycolysis as described above [75]. Here SIRT1 and AMPK comprise a reciprocal positive regulating loop. AMPK activates SIRT1 by up-regulating the gene encoding the NAD+ synthetic enzyme, NAMPT [78,79]. Reciprocally SIRT1 activates AMPK by deacetylating LKB1 [80]. In WAT, SIRT1 mobilizes fat from WAT via PPARγ to drive lipid utilization in liver and muscle [83]. In addition, by deacetylating PPARγ to facilitate Prdm16 binding, SIRT1 drives a white fat browning to enhance energy expenditure [84]. SIRT1 protein is degraded post high fat diet challenge by activated caspase I [29] and can be up-regulated by adiponectin [82]. SIRT1 also benefits the heart by increasing ischemic tolerance via an activation of eNOS [85]. SIRT1 additionally protects against cardiac hypertrophy through PPARα activation [87]. Targets that are directly activated by SIRT1 are shown in green. Those are repressed or inhibited by SIRT1 are in pink.

Figure 2. SIRT1 regulates metabolic functions centrally through the hypothalamus

This figure indicates major regions in the mouse hypothalamus that are influenced by SIRT1: dorsomedial hypothalamus (DMH), ventromedial hypothalamus (VMH), lateral hypothalamus (LH), arcuate nucleus (ARC), agouti related peptide producing neurons(AgRP), proopiomelanocortin neurons(POMC) and suprachiasmatic nucleus (SCN). High levels of SIRT1 in DMH and LH promote physical activity and increased body temperature [93]. In POMC neurons, loss of SIRT1 causes susceptibility to diet induced obesity [94]. In addition, SIRT1 regulates feeding and ghrelin response through the AgRP neurons and VMH to counter diabetes [–97]. In the SCN, SIRT1 assures robust central circadian control by increasing the amplitude of the indicated machinery of the clock [99]