Role of hepatic transporters in prevention of bile acid toxicity after partial hepatectomy in mice

Abstract

The enterohepatic recirculation of bile acids (BAs) is important in several physiological processes. Although there has been considerable research on liver regeneration after two-thirds partial hepatectomy (PHx), little is known about how the liver protects itself against BA toxicity during regeneration. In this study, various BAs in plasma and liver, the composition of micelle-forming bile constituents, as well as gene expression of the main hepatobiliary transporters were quantified in sham-operated and PHx mice 24 and 48 h after surgery. PHx did not influence the hepatic concentrations of taurine-conjugated BAs (T-BA) but increased the concentration of glycine-conjugated (G-BA) and unconjugated BAs. Total BA excretion (microg x min(-1) x g liver wt(-1)) increased 2.4-fold and was accompanied by a 55% increase in bile flow after PHx. The plasma concentrations of T-BAs (402-fold), G-BAs (17-fold), and unconjugated BAs (500-fold) increased. The mRNA and protein levels of the BA uptake transporter Ntcp were unchanged after PHx, whereas the canalicular Bsep protein increased twofold at 48 h. The basolateral efflux transporter Mrp3 was induced at the mRNA (2.6-fold) and protein (3.1-fold) levels after PHx, which may contribute to elevated plasma BA and bilirubin levels. Biliary phospholipid excretion was nearly doubled in PHx mice, most likely owing to increased mRNA expression of the phospholipid transporter, Mdr2. In conclusion, the remnant liver after PHx excretes 2.5-fold more BAs and three times more phospholipids per gram liver than the sham-operated mouse liver. Upregulation of phospholipid transport may be important in protecting the biliary tract from BA toxicity during PHx.

Alterations in hepatic lobar function in regenerating rat liver

“…After portal vein ligation, all the portal blood arriving from the splanchnic organs is directed into the PVNL lobes as a result of which there is a significant increase in the amount of recirculating bile acids per gram liver [27]. Because bile acids are toxic at high concentrations, hepatocytes need to adapt to this challenge by increasing the biliary secretion of bile acids [24]. Under normal conditions, only periportal hepatocytes are involved in bile acid secretion; however, during liver regeneration, midzonal and pericentral hepatocytes also participate in bile acid transport [28].…”

The Role of Canalicular ABC Transporters in Cholestasis

“…Both LPAC and ICP are treated with UDCA, which prevents gallstone formation in LPAC and improves symptoms and liver biochemistry in ICP. Bile duct ligation or partial hepatectomy only slightly enhanced ABCB4 expression in mice (Stedman et al, 2006;Csanaky et al, 2009), whereas TPN decreased ABCB4 expression in rats (Nishimura et al, 2005). Several other cellular stress conditions (e.g., endotoxin treatment) were not associated with an altered ABCB4 expression in animal studies (Vos et al, 1998).…”

Metabolic Characterization of Hepatocellular Carcinoma Using Nontargeted Tissue Metabolomics

“…The metabolism of cholesterol and phospholipids is a primary function of normal liver cells, and the downregulated synthesis of bile acids may lead to the malabsorption of lipids. The significant increases in taurine and 4-hydroxythreonine and decreases in urobilinogen and glycine-conjugated bile compounds in hepatocellular carcinoma suggested that the co-metabolism of gut microbes was altered in hepatocellular carcinoma, and potential changes in the enterohepatic circulation may also have occurred (31). Moreover, bile acids are closely correlated with lipids, which may cause potential regulatory effects on nuclear receptors (32).…”