Control of carbohydrate and lipid metabolism by NRF-1 and sirtuins: Implications on type 2 diabetes and obesity

Abstract

The pathogenesis of obesity, insulin resistance and type 2 diabetes can be traced to impaired carbohydrate and lipid metabolism. Carbohydrate and lipid metabolism heavily depend on the mitochondria, which itself is regulated by NRF-1. These metabolic pathways are controlled through the metabolic alterations in concentrations of high energy compounds such as the AMP/ATP and the NAD⁺/NADH ratios. Decreased concentrations of ATP are able to activate AMPK which in turn activate a versatile transcription factor, NRF-1. The function of NRF-1 is to regulate both carbohydrate and lipid metabolism. On the other hand, changes in the NAD⁺/NADH ratios affect the activity of other metabolic regulators such as the protein deacetylases called sirtuins. It has been established that sirtuins can increase the activity of the transcriptional coactivator, PGC-1, through deacetylation, the main coactivator of NRF-1. It has however not yet been established whether sirtuins can directly regulate the activity of NRF-1.  This review explores this possibility in relation to carbohydrate and lipid metabolism.