APF/CBP, an anionic polypeptide in bile and gallstones that may regulate calcium salt and cholesterol precipitation from bile

Abstract

The article in this issue of HE;PATOLOGY by Kestell et al.(1) is a welcome confirmation of the presence in bile and gallstones of a small anionic calcium-binding biliprotein -APFiCBP (anionic polypeptideicalcium binding protein) -origmally discovered by Lafont and her co-workers in Marseille (2, 3 ) as a result of their interest in hepatic lipoprotein transport and, later, in our laboratory in Chicago (4, 5 ) as a result of our hypothesis that gallstones are a biomineralization system (4, 6). This editorial will review the properties and possible roles of this protein in the regulation of the precipitation of calcium salts from bile (and thus in formation of all types of gallstones). I hope it will rectify the preoccupation with cholesterol precipitation that has dominated gallstone research for the past two decades. The possible role of APF/CBP in hepatic cholesterol and lipid transport will also be mentioned.Normal human bile is always thermodynamically supersaturated with the calcium salts of bilirubinate Ca(HB), (7,8) and often supersaturated with carbonate (9, 10) and cholesterol (9, 11). These calcium salts and others are present in all cholesterol gallstones, including their cores (6, 12), and in all pigment gallstones (12, 13). Thus one must ask, as with cholesterol (141, what inhibits precipitation of these calcium salts from normal bile and what promotes their precipitation to form gallstones in pathological bile (12). Normal bile contains a preponderance of lunetic factors that potently inhibit cholesterol precipitation ( 15). whereas pathological bile contains a preponderance of factors that potently promote (16) cholesterol Precipitation. The major kinetic factors for cholesterol are an array of bile glycoproteins, including mucin (17), that promote (17-20) or inhibit (15, 21, 22) nucleation, or growth, of cholesterol crystals. Though calcium is not required for the lunetic effects of bile proteins on cholesterol precipitation t23), variations in [Ca" 1 modulate these effects ( 2 4 ) ; however, it is not known whether t.hese proteins interact with Ca2Although bile contains factors that inhibit precipitation of calcium salts (25-28~, only one bileigallstone protein with such an effect has been described. Our This work was supported by a Medical Investigator Award from thr I! S Department of Veterans Affairs and hy extramural research grant 2-KOI-DK-32130 from the National Institutes of Health Address reprint requests to. J. Donald Ostrow. M.D.. Medical Investigator. Research Service (151). D.V.A. Lakeside iMedic-al Center.

Involvement of osteopontin as a core protein in cholesterol gallstone formation

“…Such matrix proteins have been reported in pancreatic and renal calculi []. A low‐molecular‐weight (<12kDa) acidic glycoprotein isolated from hepatic bile, gallbladder bile, cholesterol gallstones, and pigment stones, denoted an anionic polypeptide/calcium‐binding protein (APF/CBP), has been found to display calcium‐binding properties [].…”

Phosphatidylcholine-enriched diet prevents gallstone formation in mice susceptible to cholelithiasis

“…It has been demonstrated that APF is involved in the uptake of unesterified cholesterol (15) and stimulates cholesterol and PL transport to the bile (16,17). It was also recently demonstrated that APF plays an important role in controlling the onset and rates of precipitation of calcium salts, bile pigments, and cholesterol in gallstone formation (18,19).…”

Cholesterol crystallisation in bile

“…As it is found in hepatic bile, this factor is likely to be of hepatic origin. Other non-mucin factors have crystallisation promoting effects in vitro: a pronase resistant low density lipoprotein particle (±90% lipid),42 aminopeptidase N (a 130 kDa biliary canalicular glycoprotein),43 44 phospholipase C,45immunoglobulins of the IgM, IgA and IgG classes,46-48fibronectin,49 a biliary anionic polypeptide fraction (APF),50 acute phase proteins, such as a 42 kDa α 1 -acid glycoprotein,51-54α 1 -antichymotrypsin, 55 and haptoglobin. 56 Although the liver secretes promoting and inhibiting factors simultaneously, the ultimate pathophysiological importance of these proteins in human bile remains controversial 51.…”