NAD metabolism and the SLC34 family: evidence for a liver-kidney axis regulating inorganic phosphate

Abstract

The solute carrier 34 (SLC34) family of membrane transporters is a major contributor to Pi homeostasis. Many factors are involved in regulating the SLC34 family. The roles of the bone mineral metabolism factors parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) in Pi homeostasis are well studied. Intracellular Pi is thought to be involved in energy metabolism, such as ATP production. Under certain conditions of altered energy metabolism, plasma Pi concentrations are affected by the regulation of a Pi shift into cells or release from the tissues. We recently investigated the mechanism of hepatectomy-related hypophosphatemia, which is thought to involve an unknown phosphaturic factor. Hepatectomy-related hypophosphatemia is due to impaired nicotinamide adenine dinucleotide (NAD) metabolism through its effects on the SLC34 family in the liver-kidney axis. The oxidized form of NAD, NAD, is an essential cofactor in various cellular biochemical reactions. Levels of NAD and its reduced form NADH vary with the availability of dietary energy and nutrients. Nicotinamide phosphoribosyltransferase (Nampt) generates a key NAD intermediate, nicotinamide mononucleotide, from nicotinamide and 5-phosphoribosyl 1-pyrophosphate. The liver, an important organ of NAD metabolism, is thought to release metabolic products such as nicotinamide and may control NAD metabolism in other organs. Moreover, NAD is an important regulator of the circadian rhythm. Liver-specific Nampt-deficient mice and heterozygous Nampt mice have abnormal daily plasma Pi concentration oscillations. These data indicate that NAD metabolism in the intestine, liver, and kidney is closely related to Pi metabolism through the SLC34 family. Here, we review the relationship between the SLC34 family and NAD metabolism based on our recent studies.

Early Postoperative Serum Phosphate Drop Predicts Sufficient Hypertrophy after Liver Surgery

“…However, others suggest that posthepatectomy hypophosphatemia primarily relies on the action of phosphaturic factors. [37][38][39][40] In the literature, there are contrary reports on the effects of hypophosphatemia following major hepatectomy. 41 Although hypophosphatemia was associated with inferior outcomes after hepatectomy in some studies, 31,33,[42][43][44][45] other reports including ours demonstrated the superior outcome of postoperative hypophosphatemia along with poor outcome in the absence of postoperative hypophosphatemia.…”

“…Therefore, liver regeneration appears to be the dominant phosphate consumer for hepatectomy-related hypophosphatemia although the exact contribution of postoperative hyperphosphaturia remains unclear. However, others suggest that posthepatectomy hypophosphatemia primarily relies on the action of phosphaturic factors 37–40 …”

Clinical aspects of the phosphate transporters NaPi-IIa and NaPi-IIb: mutations and disease associations

“…A common metabolite of both substances is NAD + which has been shown to directly (and maybe also indirectly) inhibit renal and intestinal Pi transport [46]. Very recent evidence suggests that NAD + mediates at least in part the circadian regulation of renal and intestinal Pi transporters [71,92]. On-going clinical trials test the efficacy of nicotinamide in combination with conventional phosphate binders in the NOPHOS (EU Clinical Trials Register 2013-000488-95) and COMBINE (ClinicalTrials.gov Identifier: NCT02258074) trials.…”

Regulation of Phosphate Transporters and Novel Regulator of Phosphate Metabolism

“…In this regard, hormones such as insulin and glucagon regulate the tissue transfer of Pi, thereby affecting the blood Pi concentration. Furthermore, the circadian rhythm of the blood Pi concentration has been reported to be regulated by renal nicotinamide adenine dinucleotide metabolism, which is dependent on food intake [8][9][10]. Pi absorption/reabsorption and movement of Pi into and out of the cells are promoted by increasing or decreasing the expression levels of Pi transporters localized at cell membranes.…”