Impaired Hepatic Uptake by Organic Anion-Transporting Polypeptides Is Associated with Hyperbilirubinemia and Hypercholanemia in Atp11c Mutant Mice

Abstract

Biliary excretion of organic anions, such as bile acids (BAs), is the main osmotic driving force for bile formation, and its impairment induces intrahepatic cholestasis. We investigated the involvement of Atp11c in the hepatic transport of organic anions using Atp11c mutant mice, which exhibit hypercholanemia and hyperbilirubinemia. Pharmacokinetic analysis following a constant intravenous infusion in Atp11c mutant mice showed decreased hepatic sinusoidal uptake and intact biliary secretion of [ 3 H]17b estradiol 17b-D-glucuronide. Consistent with this result, compared with cells and membranes from control mice, isolated hepatocytes, and liver plasma membranes from Atp11c mutant mice had a much lower uptake of [ 3 H]17b estradiol 17b-Dglucuronide and expression of organic anion-transporting polypeptides, which are transporters responsible for hepatic uptake of unconjugated BAs and organic anions, including bilirubin glucuronides. Uptake of [ 3 H]TC into hepatocytes and expression of Na 1 -taurocholate cotransporting polypeptide in liver plasma membranes, which mediates hepatic uptake of conjugated BAs, was also lower in the Atp11c mutant mice. Bile flow rate, biliary BA concentration, and expression of hepatobiliary transporters did not differ between Atp11c mutant mice and control mice. These results suggest that Atp11c mediates the transport of BAs and organic anions across the sinusoidal membrane, but not the canalicular membrane, by regulating the abundance of transporters. Atp11c is a candidate gene for genetically undiagnosed cases of hypercholanemia and hyperbilirubinemia, but not of intrahepatic cholestasis. This gene may influence the pharmacological and adverse effect of drugs because organic anion-transporting polypeptides regulate their systemic exposure.

Blocking Sodium‐Taurocholate Cotransporting Polypeptide Stimulates Biliary Cholesterol and Phospholipid Secretion in Mice

“…Atp11c ‐deficient mice are a model with a zonation difference in bile salt uptake given that basolateral bile salt uptake transporters are absent in the pericentral region restricting bile salt uptake to periportal regions, where NTCP expression is maintained in the periportal hepatocyte (Fig. E) . In this experiment, the relation between biliary cholesterol and bile salt levels was not significantly different between Atp11c‐ deficient mice and WT littermates under conditions where the periportal region predominates uptake (before TC infusion).…”

Disposition of flavonoids via recycling: Direct biliary excretion of enterically or extrahepatically derived flavonoid glucuronides

“…Although hepatocytes have been shown to take up glucuronides, the molecular mechanisms responsible for their uptake are only recently becoming clear, albeit seldom specifically for flavonoid glucuronides . For example, OATPs were involved in the uptake of steroid conjugate estradiol‐glucuronide via OATP1b2 and 1a4 , of gemfibrozil‐1‐O‐β‐glucuronide via OATP1B1, 1B3, and 2B1 , of ezetimibe glucuronide via OATP1B1 and 2B1 , of scutellarein‐7‐O‐glucuronide via OATP2B1 , and of raloxifene‐glucuronides via OATP1B1 and OATP1B3 . However, these studies are usually conducted using cells overexpressing various hepatic transporters, and as such it is difficult to gauge the actual contribution of each of the OATPs in vivo.…”

“…In a study conducted in vivo using Atp11c mutant mice, which has very significantly reduced (>80% decrease) expression of OATP1b2 and 1a4, clearance of 17β‐estradiol‐glucuronide was reduced less than 50% and its steady‐state concentration was increased only two‐fold. Hence, we cannot exclude the possibility that other uptake transporters might be involved in flavonoid glucuronide uptake by the hepatocytes .…”

Exposure of phosphatidylserine on the cell surface

“…Lymphocytes or erythrocytes might express only the ATP11C flippase at a specific developmental stage; an ATP11C-null mutation may cause the PtdSer exposure in cells at this stage, leading macrophages to recognize and engulf these cells or causing the destabilization and abnormal assembly of plasma-membrane proteins. 90,91 Scott syndrome, a mild autosomal bleeding disorder, is caused by the failure of Ca 2+ -dependent PtdSer exposure in activated platelets. 92 Patients in two families carrying Scott syndrome had a homozygous null mutation or compound heterozygous mutations in the TMEM16F gene.…”