ABCG5/ABCG8-independent biliary cholesterol excretion in lactating rats

Abstract

Lactation is associated with increased expression of bile acid transporters and an increased size and hydrophobicity of the bile acid pool in rats. ATP-binding cassette (ABC) transporters multidrug resistance protein 2 (Mdr2), Abcb11 [bile salt export pump (Bsep)], and Abcg5/Abcg8 heterodimers are essential for the biliary secretion of phospholipids, bile acids, and cholesterol, respectively. We investigated the expression of these transporters and secretion of their substrates in female control and lactating Sprague Dawley rats and C57BL/6 mice. Expression of Abcg5/Abcg8 mRNA was decreased by 97 and 60% by midlactation in rats and mice, respectively; protein levels of Abcg8 were below detection limits in lactating rats. Mdr2 mRNA expression was decreased in lactating rats and mice by 47 and 59%, respectively. Despite these changes in transporter expression, basal concentrations of cholesterol and phospholipid in bile were unchanged in rats and mice, whereas increased Bsep mRNA expression in early lactation coincided with an increased basal biliary bile acid concentration in lactating mice. Following taurocholate infusion, coupling of phospholipid and taurocholate secretion in bile of lactating mice was significantly impaired relative to control mice, with no significant changes in maximal secretion of cholesterol or bile acids. In rats, taurocholate infusion revealed a significantly impaired coupling of cholesterol to taurocholate secretion in bile in lactating vs. control animals. These data reveal marked utilization of an Abcg5/Abcg8-independent mechanism for basal biliary cholesterol secretion in rats during lactation, but a dependence on Abcg5/g8 for maximal biliary cholesterol secretion.

Differential gene expression in liver and small intestine from lactating rats compared to age-matched virgin controls detects increased mRNA of cholesterol biosynthetic genes

“…Abcg5 and Abcg8 show decreased levels of mRNA expression in the liver and ileum. A decrease in the concentration of active Abcg5/Abcg8 heterodimer in the intestine would be expected to yield an increase in net cholesterol uptake through decreased efflux from the enterocyte into the gut lumen, while decreased hepatic expression would minimize cholesterol secretion into bile [ 51 ]. The decreased expression of Abcg5/g8 mRNA in the liver, together with increased expression of cholesterol synthetic genes, likely serve to enhance conservation of cholesterol to allow for sufficient transfer of cholesterol into the milk and for synthesis of bile acids.…”

Pravastatin modulates liver bile acid and cholesterol homeostasis in rats with chronic cholestasis

“…However, significant induction of cholesterol biliary secretion in our treated controls and its reduction in BDO‐P5 suggest another mechanism. Indeed, several authors recently demonstrated that modulation of cholesterol biliary excretion is not necessarily associated with changed expression of these transporters 28–31 . Oude Elferink et al 32 .…”

“…Indeed, several authors recently demonstrated that modulation of cholesterol biliary excretion is not necessarily associated with changed expression of these transporters. [28][29][30][31] Oude Elferink et al 32 showed that the main driving force for the secretion of cholesterol into bile is biliary secretion of bile acids. We, therefore, hypothesize that changes in cholesterol biliary excretion in our study are attributable to the corresponding decrease (BDO-P5 group) or increase (control pravastatin group) in bile acid biliary secretion and bile flow through modulation of Bsep.…”

Mechanism of rapid elimination of lysophosphatidic acid and related lipids from the circulation of mice

“…Single-pass rat liver perfusion was performed as previously described ( 15 ). Mice were anesthetized with urethane (1g/kg ip).…”