Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied

Abstract

Alkaline sphingomyelinase cleaves phosphocholine from sphingomyelin, platelet-activating factor, lysophosphatidylcholine, and less effectively phosphatidylcholine. The enzyme shares no structure similarities with acid or neutral sphingomyelinase but belongs to ecto-nucleotide pyrophosphatase/phosphodiesterase (NPP) family and therefore is also called NPP7 nowadays. The enzyme is expressed in the intestinal mucosa in many species and additionally in human liver. The enzyme in the intestinal tract has been extensively studied but not that in human liver. Studies on intestinal alkaline sphingomyelinase show that it inhibits colonic tumorigenesis and inflammation, hydrolyses dietary sphingomyelin, and stimulates cholesterol absorption. The review aims to summarize the current knowledge on liver alkaline sphingomyelinase in human and strengthen the necessity for close study on this unique human enzyme in hepatobiliary diseases.

Keywords: Alkaline sphingomyelinase; Autotaxin; Cholangiocarcinoma; Gallstone; Liver diseases; Nucleotide pyrophosphatase/phosphodiesterase 7; Platelet-activating factor; Sphingomyelin.

Figure 1

Metabolism of sphingomyelin in the liver and potential implications of alk-SMase in liver diseases. Liver alk-SMase is localized on the hepatocyte canaliculi membrane. It hydrolyzes SM, PAF, and lyso-PC, resulting in increased ceramide (Cer) and decreased PAF and LPA, thus having anticancer and anti-inflammatory effects. Together with PC, cholesterol, and bile salts, SM is released in canaliculi and transported to gallbladder, where the interactions of these compounds affect gallstone formation. When the bile is delivered into the intestinal tract, bile salt will release additional alk-SMase from intestinal mucosa, and digest intestinal SM to ceramide and phosphocholine (Pch). Meanwhile, PC will be hydrolyzed by enzymes from pancreas and intestinal mucosa to choline compounds such as free choline, lyso-PC, and Pch. These choline compounds will be transported to liver where to be used for synthesis of PC. Pch moiety in PC can be transferred to ceramide to form SM by SM synthases. Part of the SM formed will be released into blood together with lipoproteins, part to bile, and part to be degraded by alk-SMase and acid SMase (ASMase) in the liver.