The role of sirtuins in the control of metabolic homeostasis

Abstract

Recently the function of the sirtuin family, named after their homology to the Saccharomyces cerevisiae gene silent information regulator 2 (Sir2), has received a lot of attention, as their beneficial impact on longevity was linked to their effects on metabolic control. All sirtuins require nicotinamide adenine dinucleotide (NAD(+)) for their deacetylase or ADP-ribosyl transferase activity, linking their function tightly to cellular energy levels. SIRT1, the founding member of the sirtuin family, modulates many aspects of glucose and lipid homeostasis in almost all key metabolic tissues. Other members including SIRT2, SIRT3, and SIRT4 are also implicated in various metabolic processes. Here, we review the recent data related to the role of sirtuins in the control of metabolic homeostasis and possible underlying molecular mechanisms.

Figure 1

The diverse functions of SIRT1 in different metabolic tissues. SIRT1 promotes gluconeogenesis through PGC-1α and possibly FOXO1 in the liver upon fasting. SIRT1 also facilitates fatty acid oxidation through PGC-1α and cholesterol scavenging through LXRs in the liver. In WAT, SIRT1 inhibits the adipogenesis process and blocks fat storage mainly by serving as a corepressor of PPARγ. In BAT, SIRT1 increases the mitochondrial activity in cells and improves the thermogenic capacity of BAT in a PGC-1α-dependent manner. SIRT1 also functions as the corepressor of PPARγ on the promoter of UCP-2 gene in the pancreas. Inhibition of UCP-2 protein expression enhances ATP production and subsequent insulin secretion in β cells. SIRT1 blocks myogenesis partially through reducing MyoD activity. In the mature skeletal muscle, SIRT1 activation leads to an increase in mitochondrial activity, fatty acid oxidation, and insulin sensitivity. SIRT1 activity itself is regulated by multiple modulator proteins. The nuclear protein AROS is suggested to promote the deacetylase activity of SIRT1, whereas another SIRT1-interacting protein DBC1 inhibits SIRT1 activity. The desumoylase SENP1 desumoylates and subsequent inactivates SIRT1.

Figure 2

The involvement of other sirtuins in the metabolic homeostasis. SIRT2 inhibits the differentiation of white preadipocytes. It achieves this effect likely through deacetylating FOXO1. Thus FOXO1 is retained on the target promoters of PPARγ and inhibits PPARγ-mediated transcription of genes that drive adipogenesis. In brown adipocytes, SIRT3 promotes the expression of mitochondrial-related genes in a PGC-1α-dependent manner and results in enhanced mitochondrial activity. SIRT4 ADP-ribosylates the mitochondrial enzyme GDH, which positively regulates ATP generation and insulin secretion in the pancreas. The resulting ADP-ribosylation inhibits the activity of GDH. Therefore, SIRT4 serves as a negative regulator for insulin secretion in the pancreas.