TNAP: A New Multitask Enzyme in Energy Metabolism

Abstract

Tissue-nonspecific alkaline phosphatase (TNAP) is mainly known for its necessary role in skeletal and dental mineralization, which relies on the hydrolysis of the mineralization inhibitor inorganic pyrophosphate (PP_i). Mutations in the gene encoding TNAP leading to severe hypophosphatasia result in strongly reduced mineralization and perinatal death. Fortunately, the relatively recent development of a recombinant TNAP with a bone anchor has allowed to correct the bone defects and prolong the life of affected babies and children. Researches on TNAP must however not be slowed down, because accumulating evidence indicates that TNAP activation in individuals with metabolic syndrome (MetS) is associated with enhanced cardiovascular mortality, presumably in relation with cardiovascular calcification. On the other hand, TNAP appears to be necessary to prevent the development of steatohepatitis in mice, suggesting that TNAP plays protective roles. The aim of the present review is to highlight the known or suspected functions of TNAP in energy metabolism that may be associated with the development of MetS. The location of TNAP in liver and its function in bile excretion, lipopolysaccharide (LPS) detoxification and fatty acid transport will be presented. The expression and function of TNAP in adipocyte differentiation and thermogenesis will also be discussed. Given that TNAP is a tissue- and substrate-nonspecific phosphatase, we believe that it exerts several crucial pathophysiological functions that are just beginning to be discovered.

Keywords: CD36; TNAP; adipocyte; bile; lipopolysaccharide; liver; metabolic syndrome; phosphocreatine; steatosis.

Figure 1

Location of TNAP in the liver. (A) Rough presentation of the liver structure indicating the region presented in (B). (B) Typical organization of hepatocytes and cholangiocytes delimitating bile ducts and liver vascularization showing TNAP location in hepatic artery. (C) Detail of (B) showing TNAP location in hepatocyte membranes facing bile canaliculi.

Figure 2

Function of TNAP in bile excretion (A) Rough presentation of liver structures indicating the region presented in (B). (B) Typical organization of hepatocytes delimitating bile canaliculi, showing from the top to the bottom the sequence of molecular events involved in pH regulation during bile excretion.

Figure 3

Schematic representation of CD36, showing its intracellular, transmembrane, and extracellular domains including posttranslational modification sites [47]. G: glycosylation sites (CD36 glycosylation is permanent and necessary for proper protein folding); P: phosphorylation site; S: cysteine involved in a disulfide bond; U: ubiquitination site.

Figure 4

Sources of liver phosphatidylcholine showing the two main pathways allowing hepatocytes to produce phosphatidylcholine. On the right, phosphatidylcholine generation after the cellular uptake of choline arising from the diet or lipoproteins; on the left, generation of phosphatidylcholine from PEA. The phosphatase(s) generating choline and ethanolamine extracellularly are not known and may include TNAP. CDP: cytidine diphosphate; CTP: cytidine triphosphate; LCAT; lecithin cholesterol acyltransferase; NPP: nucleotide pyrophosphatase/phosphodiesterases PLA₂; phospholipase A₂.

Figure 5

Schematic representation of the mitochondrial electron transport chain showing TNAP’s involvement in the futile creatine cycle. (A) indicates that the molecules and reactions presented in (B) are present at the inner mitochondrial membrane, in the intermembrane space, and possibly in the cytoplasm (it is still obscure where exactly TNAP may dephosphorylate phosphocreatine). I to IV represent complex I to complex IV. CK: creatine kinase; CytC: cytochrome C; FAD: flavine adenine dinucleotide; IMS: intermembrane space; NAD: nicotinamide adenine dinucleotide; Q: coenzyme Q.