Fig. 7.

Pathophysiological role of NAD⁺ disarrangement in metabolic diseases. a The liver is a master organ of NAD⁺ metabolism and may facilitate the NAD⁺ biosynthesis in other tissues. NAD⁺ metabolism plays a critical role in the lipid metabolism through modulating the activity of sirtuins. The reduced NAMPT expression and NAD⁺ levels contribute to the development of NAFLD through manipulating dysmetabolic imbalance, hepatic energy homeostasis, glucose homeostasis, hepatic inflammation and insulin resistance. b Decreased NAD⁺/NADH ratio by the mismatch between NADH production and oxidation inhibits the activity of sirtuins in the failing heart. Elevated protein acetylation weakens the energy metabolism through negative feedback to OXPHOS and substrate metabolism, impairing antioxidant defense and sensitizing the mPTP to ROS or calcium. c The deduced NAD⁺ levels in kidney are attributed to the decreased expression of enzymes in NAD⁺ de novo synthesis and increased consumption by DNA damage activated PARPs. NAD⁺ depletion inhibits the SIRT1/PGC1α mediated mitochondrial quality control, ATP production and NAD⁺ de novo biosynthesis. The phosphorylation of NAD⁺ to NADP⁺ enhances the antioxidant defense against oxidant stress. NAD⁺-dependent defect in FAO results in intracellular lipid accumulation. In addition, the defected FAO and increased desaturation of PUFAs to HUFAs due to NAD⁺ deficiency and impaired mitochondrial function result in the accumulation of HUFA-containing triglycerides and cellular lipid in renal tubular cells. d The insulin secretion is adjusted by the dynamic glucose concentration in blood. As a master regulator of insulin secretion, glucose is metabolized via the glycolysis and TCA cycle to produce NADH and ATP. The increased NADH and ATP induces the closure of ATP-dependent K⁺ channels, the opening of voltage-gated L-type Ca²⁺ channels, the raising of cytosolic Ca²⁺ and culminating in insulin secretion in pancreatic β-cells. The activity of mitochondrial shuttles including the glycerophosphate and malate/aspartate shuttles allows the reoxidation of cytosolic NADH into NAD⁺, which is required for maintenance of the glycolysis. Purple representants the downregulated proteins or activated biological functions, while brown labels the upregulated proteins and repressed physiological activities. Abbreviations: ACMSD, alpha-amino-beta-carboxy-muconate-semialdehyde decarboxylase; AR, Aldose reductase; ETC, electron transport chain; Grxs, glutaredoxins; HUFAs, highly unsaturated fatty acids; KMO, kynurenine 3-monooxygenase; FAO, fatty acid oxidation; PUFAs, polyunsaturated fatty acids; SDH, Sorbitol dehydrogenase; Trxs, thioredoxins. 3-HK, 3-hydroxykynurenine