Liver cell membrane solubilization may control maximum secretory rate of cholic acid in the rat

Abstract

The factors modulating the maximum secretory rate of cholic acid were investigated. Rats were infused intravenously with cholic acid in measured stepwise increasing doses (1, 2, 3, and 4 mumol X min-1 X 100 g body wt-1). Each dose was infused for 30 min and bile samples were collected every 10 min. Bile flow, bile acid, cholesterol, individual biliary phospholipids, and the fatty acid profiles of the biliary phospholipids were determined. Microsomal and bile canalicular membrane-enriched fractions were isolated from cholic acid-treated rats at the end of the experiment. Membranes were analyzed for cholesterol, phospholipid, and phospholipid fatty acid composition. During cholic acid infusion, the secretion rates of bile acid, cholesterol, phospholipid, and bile flow initially increased and then declined. No evidence of liver cell damage was observed by light or electron microscopy. Maximum phospholipid secretion rate (13.5 nmol X min-1 X g-1) occurred before peak bile flow and bile acid secretory rate maximum (4.72 microliter X min-1 X g-1 and 375 nmol X min-1 X g-1). When phospholipid output declined, the proportion of sphingomyelins and phosphatidylethanolamine relative to phosphatidylcholine increased. This was also reflected in the fatty acid composition. Cholic acid infusion caused a decline in microsomal and bile canalicular membrane phospholipid content without affecting their phospholipid composition. Depletion of membrane phospholipid resulted in an increase in the cholesterol:phospholipid ratio, which is suggested to be the underlying mechanism for modulating cholic acid secretion.

The phosphatidylethanolamine N-methyltransferase pathway is quantitatively not essential for biliary phosphatidylcholine secretion

“…The amount of PC secreted into bile is influenced by several factors (20): 1) the intracanalicular bile salt concentration (21,22); 2) the hydrophobicity of the intracanalicular bile salts (23); 3) the magnitude of the bile salt-independent fraction of the bile flow (24); 4) the concentration of hydrophilic organic anions (25); 5) the abundance of Mdr2 at the bile canalicular membrane (3,16,26); and 6) the lipid composition of the bile canalicular membrane (27)(28)(29)(30). Taurocholate feeding did not induce detectable changes in Mdr2 mRNA or protein levels (Fig.…”

Abcg5/Abcg8-independent pathways contribute to hepatobiliary cholesterol secretion in mice

“…Upon the infusion of hydrophobic BSs, typically PL secretion declined first, followed by decreases in bile flow, BS output, and cholesterol output. Concomitantly with the decline in PL output, the PL composition changed from mainly phosphatidylcholine to more phosphatidylethanolamine and sphingomyelins, which was attributed to partial solubilization of the canalicular membrane (38). On the basis of these results, these authors concluded that an insufficient supply of phosphatidylcholine to the canalicular plasma membrane was the cause of BS-induced cholestasis.…”

Regulation of MDR2 P-glycoprotein expression by bile salts

“…Several studies describe a hyperbolic relationship between bile salt secretion and phospholipid or cholesterol secretion [6,10]. An increase in bile salt output leads to an increase in phospholipid and cholesterol secretion until a certain plateau is reached [11,12]. Furthermore, it has become Abbreviations used : GADPH, glyceraldehyde-3-phosphate dehydrogenase ; Pgp, P-glycoprotein ; TUDC, tauroursodeoxycholate ; UDC, ursodeoxycholate.…”