Human hepatitis B virus (HBV) infection and HBV-related diseases remain a major public health problem. Individuals coinfected with its satellite hepatitis D virus (HDV) have more severe disease. Cellular entry of both viruses is mediated by HBV envelope proteins. The pre-S1 domain of the large envelope protein is a key determinant for receptor(s) binding. However, the identity of the receptor(s) is unknown. Here, by using near zero distance photo-cross-linking and tandem affinity purification, we revealed that the receptor-binding region of pre-S1 specifically interacts with sodium taurocholate cotransporting polypeptide (NTCP), a multiple transmembrane transporter predominantly expressed in the liver. Silencing NTCP inhibited HBV and HDV infection, while exogenous NTCP expression rendered nonsusceptible hepatocarcinoma cells susceptible to these viral infections. Moreover, replacing amino acids 157-165 of nonfunctional monkey NTCP with the human counterpart conferred its ability in supporting both viral infections. Our results demonstrate that NTCP is a functional receptor for HBV and HDV.

/pdf/sodium-taurocholate-cotransporting-polypeptide-is-a-a1qcwcj9nz.pdf

Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus

https://www.naspghan.org/files/documents/pdfs/training/curriculum-resources/biliary-disease/aasld-guidelines/EASL_Cholestatic_Dz.pdf

EASL Clinical Practice Guidelines: management of cholestatic liver diseases

This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.

/pdf/recent-advances-in-2d-and-3d-in-vitro-systems-using-primary-46n7hrqknx.pdf

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.

https://www.journal-of-hepatology.eu/article/S0168-8278(17)30186-1/pdf

EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis

Molecular medicine has led to rapid advances in the characterization of hepatobiliary transport systems that determine the uptake and excretion of bile salts and other biliary constituents in the l...

https://www.physiology.org/doi/pdf/10.1152/physrev.00027.2002

Bile Salt Transporters: Molecular Characterization, Function, and Regulation

Chlorambucil-taurocholate is transported by bile acid carriers expressed in human hepatocellular carcinomas.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/S0014-5793%2898%2900168-9

Dehydroepiandrosterone sulfate (DHEAS): identification of a carrier protein in human liver and brain.

BACKGROUND/AIMS In chronic cholestatic liver diseases, biliary excretion of organic anions from blood into bile is impaired. The aim of this study was to identify the underlying mechanism. METHODS Expression of the basolateral organic anion transporting polypeptide OATP-C (SLC21A6) and the canalicular multidrug resistance protein 2 (MRP2) was studied in patients with primary sclerosing cholangitis (PSC) (n=4), a chronic cholestatic liver disease, and in non-cholestatic controls (n=4) (two with chronic hepatitis C, one with idiopathic liver cirrhosis and one with fatty liver). Total RNA was isolated from liver tissue, reverse transcribed and subjected to polymerase chain reaction (PCR) amplification using primers specific for OATP-C, MRP2 and beta-actin. PCR products were quantified densitometrically. RESULTS When normalized for beta-actin expression, the level of OATP-C mRNA in liver tissue of patients with PSC was 49% of controls (OATP-C/beta-actin 1.60+/-0.25 vs. 3.24+/-0.69; p<0.05) and the level of MRP2 mRNA was 27% of controls (MRP2/beta-actin 0.70+/-0.36 vs. 2.54+/-0.56; p<0.01). CONCLUSIONS Both OATP-C and MRP2 are decreased as measured by mRNA level in PSC. Downregulation of OATP-C might be the consequence of impaired canalicular secretion of organic anions and could serve to reduce the organic anion load of cholestatic hepatocytes.

Expression of hepatic transporters OATP-C and MRP2 in primary sclerosing cholangitis

Background

Cholestyramine is the first-line treatment for cholestasis-induced pruritus and is prescribed along with ursodeoxycholic acid (UDCA) in patients with cholestatic liver diseases. Impairment of the intestinal absorption of endogenous hydrophobic bile acids by cholestyramine is well known. It is unclear, however, whether cholestyramine also impairs the absorption of the hydrophilic bile acid, UDCA, in man.



Aims

To study serum levels of UDCA and endogenous bile acids as well as endogenous bile acid synthesis during simultaneous or separate administration of UDCA and cholestyramine in vivo; and absorption of UDCA both in the presence and absence of its hydrophobic epimer, chenodeoxycholic acid (CDCA), by cholestyramine in vitro.



Patients and methods

Five healthy subjects received UDCA (12.5 ± 0.5 mg kg−1 daily) as a single dose for periods of 14 days with or without cholestyramine (4 g daily). Fasting serum levels of bile acids and of 7α-hydroxy-4-cholesten-3-one (α-HC), a measure of endogenous bile acid synthesis, were determined by gas chromatography and high pressure liquid chromatography, respectively. In vitro, bile acid solutions were incubated for 24 h in the presence or absence of cholestyramine, and bile acid concentrations were determined in the supernatant.



Results

Simultaneous administration of UDCA and cholestyramine in man led to a decrease of fasting serum levels of UDCA by 60% when compared to UDCA serum levels during administration of UDCA alone. In contrast, serum levels of endogenous bile acids were not affected and α-HC serum levels were found increased 2.7-fold indicating stimulation of endogenous bile acid synthesis by cholestyramine. Administration of cholestyramine and UDCA at an interval of 5 h tended to diminish the effect of cholestyramine on UDCA serum levels. In vitro, conjugated and unconjugated UDCA were effectively bound by cholestyramine both in the presence and absence of hydrophobic bile acids.



Conclusions

The results strongly support the recommendation to administer UDCA and cholestyramine at different times of day.

Effect of cholestyramine on bile acid pattern and synthesis during administration of ursodeoxycholic acid in man

Downregulation of the hepatocellular organic anion transporters OATP-C and MRP2 in patients with primary sclerosing cholangitis

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