Human and mouse alkaline
phosphatases (AP) are encoded by a multigene family expressed ubiquitously in multiple tissues. Gene knockout (KO) findings have helped define some of the precise exocytic functions of individual
isozymes in bone, teeth, the central nervous system, and in the gut. For instance, deficiency in tissue-nonspecific
alkaline phosphatase (TNAP) in mice (Alpl (-/-) mice) and humans leads to
hypophosphatasia (
HPP), an inborn error of metabolism characterized by epileptic
seizures in the most severe cases, caused by abnormal metabolism of pyridoxal-5'-phosphate (the predominant form of
vitamin B6) and by hypomineralization of the skeleton and teeth featuring
rickets and early loss of teeth in children or
osteomalacia and dental problems in adults caused by accumulation of inorganic
pyrophosphate (PPi).
Enzyme replacement therapy with
mineral-targeting TNAP prevented all the manifestations of
HPP in mice, and clinical trials with this
protein therapeutic are showing promising results in rescuing life-threatening
HPP in infants. Conversely, TNAP induction in the vasculature during generalized
arterial calcification of infancy (
GACI), type II diabetes,
obesity, and aging can cause medial
vascular calcification. TNAP inhibitors, discussed extensively in this book, are in development to prevent pathological arterial calcification. The brush border
enzyme intestinal
alkaline phosphatase (IAP) plays an important role in
fatty acid (FA) absorption, in protecting gut barrier function, and in determining the composition of the gut microbiota via its ability to dephosphorylate
lipopolysaccharide (LPS). Knockout mice (Akp3 (-/-)) deficient in duodenal-specific IAP (dIAP) become obese, and develop
hyperlipidemia and hepatic steatosis when fed a high-fat diet (HFD). These changes are accompanied by upregulation in the jejunal-ileal expression of the Akp6 IAP
isozyme (global IAP, or gIAP) and concomitant upregulation of FAT/CD36, a phosphorylated
fatty acid translocase thought to play a role in facilitating the transport of long-chain
fatty acids into cells. gIAP, but not dIAP, is able to modulate the phosphorylation status of FAT/CD36. dIAP, even though it is expressed in the duodenum, is shed into the gut lumen and is active in LPS dephosphorylation throughout the gut lumen and in the feces. Akp3 (-/-) mice display gut
dysbiosis and are more prone to
dextran sodium sulfate-induced
colitis than wild-type mice. Of relevance,
oral administration of recombinant calf IAP prevents the
dysbiosis and protects the gut from chronic
colitis. Analogous to the role of IAP in the gut, TNAP expression in the liver may have a proactive role from bacterial
endotoxin insult. Finally, more recent studies suggest that neuronal death in
Alzheimer's disease may also be associated with TNAP function on certain brain-specific
phosphoproteins. This review recounts the established roles of TNAP and IAP and briefly discusses new areas of investigation related to multisystemic functions of these
isozymes.