Both prolonged high-fat diet consumption and calorie restriction boost hepatic NAD+ metabolism in mice.

Hepatic NAD+ homeostasis is essential to metabolic flexibility upon energy balance challenges. The molecular mechanism is unclear. This study aimed to determine how the enzymes involved in NAD+ salvage (Nampt, Nmnat1, Nrk1), clearance (Nnmt, Aox1, Cyp2e1), and consumption pathways (Sirt1, Sirt3, Sirt6, Parp1, Cd38) were regulated in the liver upon energy overload or shortage, as well as their relationships with glucose and lipid metabolism. Male C57BL/6N mice were fed ad libitum with the CHOW diet, high-fat diet (HFD), or subjected to 40% calorie restriction (CR) CHOW diet for 16 weeks respectively. HFD feeding increased hepatic lipids content and inflammatory markers, while lipids accumulation was not changed by CR. Both HFD feeding and CR elevated the hepatic NAD+ levels, as well as gene and protein levels of Nampt and Nmnat1. Furthermore, both HFD feeding and CR lowered acetylation of PGC-1α in parallel with the reduced hepatic lipogenesis and enhanced fatty acid oxidation, while CR enhanced hepatic AMPK activity and gluconeogenesis. Hepatic Nampt and Nnmt gene expression negatively correlated with fasting plasma glucose levels concomitant with positive correlations with Pck1 gene expression. Nrk1 and Cyp2e1 gene expression positively correlated with fat mass and plasma cholesterol levels, as well as Srebf1 gene expression. These data highlight that hepatic NAD+ metabolism will be induced for either the down-regulation of lipogenesis upon over nutrition or up-regulation of gluconeogenesis in response to CR, thus contributing to the hepatic metabolic flexibility upon energy balance challenges.