Regulation of Glucose Metabolism by NAD+ and ADP-Ribosylation

Abstract

Cells constantly adapt their metabolic pathways to meet their energy needs and respond to nutrient availability. During the last two decades, it has become increasingly clear that NAD+, a coenzyme in redox reactions, also mediates several ubiquitous cell signaling processes. Protein ADP-ribosylation is a post-translational modification that uses NAD+ as a substrate and is best known as part of the genotoxic stress response. However, there is increasing evidence that NAD+-dependent ADP-ribosylation regulates other cellular processes, including metabolic pathways. In this review, we will describe the compartmentalized regulation of NAD+ biosynthesis, consumption, and regeneration with a particular focus on the role of ADP-ribosylation in the regulation of glucose metabolism in different cellular compartments.

The role of ADP-ribose metabolism in metabolic regulation, adipose tissue differentiation, and metabolism

“…PARP1 can PARylate and hence inhibit GAPDH (Du et al 2003). Furthermore, since GAPDH is NAD + -dependent, NAD + breakdown by cytoplasmic PARPs can limit GAPDH activity and, consequently, glycolytic flux (Hopp et al 2019). These results were confirmed by the observation that PARP1 knockout mice have higher respiratory quotient, suggesting a shift toward glucose oxidation (Bai et al 2011b).…”

“…These results were confirmed by the observation that PARP1 knockout mice have higher respiratory quotient, suggesting a shift toward glucose oxidation (Bai et al 2011b). Although pyruvate dehydrogenase complex is not considered as a member of the glycolytic enzymatic machinery, it is important to note that three subunits of the complex (PDPR, PDHA1, and PDHX) are subject to poly-ADP-ribosylation, which may regulate the fate of pyruvate, whether it can enter the TCA cycle, convert to lactate, or undergo gluconeogenesis (Hopp et al 2019). PARP10 and PARP14 are two poorly characterized members of the PARP family.…”

“…PARPs regulate points in glycolysis (Hopp et al 2019), the core pathway of glucose catabolism. PARP1 activation hampers glycolytic flux, inducing metabolic dysfunction (Ying et al 2002(Ying et al , 2003Devalaraja-Narashimha and Pada-nilam 2009;Módis et al 2012;Robaszkiewicz et al 2014).…”

“…A high-glucose or high-fructose diet can induce the expression of PARP1 (Choi et al 2017;Huang et al 2019). The interplay between carbohydrate metabolism and PARPs was extensively reviewed in Hopp et al (2019).…”

“…Nevertheless, large scale studies are missing. There are genes reported to be PARP-mediated (e.g., MDH1) (Hopp et al 2019) that regulate adipocyte differentiation. Again, the involvement of these genes in adipogenesis in the context of PARylation had not been assessed.…”