Molecular regulation of the hepatic bile acid uptake transporter and HBV entry receptor NTCP

Appelman, Monique D.; Wettengel, Jochen M.; Protzer, Ulrike; Elferink, Ronald P.J. Oude; Graaf, Stan F.J. van de

doi:10.1016/j.bbalip.2021.158960

Cited by 23 publications

(27 citation statements)

References 88 publications

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“…BSEP is a major transporter involved in the secretion of Bas from hepatocytes into bile, and this process is tightly regulated at the transcriptional and posttranscriptional levels by several liver-enriched transcription factors, for example, FXR ( Ren et al, 2021 ). NTCP is a transporter that uptakes bile acids from portal blood into hepatocytes ( Appelman et al, 2021 ). This study showed that IsA significantly increased hepatic CDCA levels and decreased T-βMCA amounts, thereby elevating hepatic FXR mRNA expression.…”

Section: Discussionmentioning

confidence: 99%

“…The activities of these enzymes are negatively regulated by the ileal FXR/fibroblast growth factor 15 (FGF15) axis. Hepatic FXR activation regulates BA levels in the liver by inducing canalicular bile salt export pump (BSEP) expression to promote BA efflux and repressing Na + /taurocholate cotransporting polypeptide (NTCP) to reduce BA uptake ( Appelman et al, 2021 ). BA metabolism and excretion are closely related to the gut microbiota.…”

Section: Introductionmentioning

confidence: 99%

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Ilexsaponin A1 Ameliorates Diet-Induced Nonalcoholic Fatty Liver Disease by Regulating Bile Acid Metabolism in Mice

Zhao

Meng

et al. 2021

Front. Pharmacol.

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Bile acid (BA) metabolism is an attractive therapeutic target in nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the effect of ilexsaponin A1 (IsA), a major bioactive ingredient of Ilex, on high-fat diet (HFD)-induced NAFLD in mice with a focus on BA homeostasis. Male C57BL/6J mice were fed an HFD to induce NAFLD and were treated with IsA (120 mg/kg) for 8 weeks. The results showed that administration of IsA significantly decreased serum total cholesterol (TC), attenuated liver steatosis, and decreased total hepatic BA levels in HFD-induced NAFLD mice. IsA-treated mice showed increased BA synthesis in the alternative pathway by upregulating the gene expression levels of sterol 27-hydroxylase (CYP27A1) and cholesterol 7b-hydroxylase (CYP7B1). IsA treatment accelerated efflux and decreased uptake of BA in liver by increasing hepatic farnesoid X receptor (FXR) and bile salt export pump (BSEP) expression, and reducing Na+-taurocholic acid cotransporting polypeptide (NTCP) expression. Alterations in the gut microbiota and increased bile salt hydrolase (BSH) activity might be related to enhanced fecal BA excretion in IsA-treated mice. This study demonstrates that consumption of IsA may prevent HFD-induced NAFLD and exert cholesterol-lowering effects, possibly by regulating the gut microbiota and BA metabolism.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ilexsaponin A1 Ameliorates Diet-Induced Nonalcoholic Fatty Liver Disease by Regulating Bile Acid Metabolism in Mice

Zhao

Meng

et al. 2021

Front. Pharmacol.

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“…Regardless of the size, these proteins share a high-amino acid sequence identity of 79% (hNTCP vs. mNtcp) and 78% (hNTCP vs. rNtcp) ( Figure 1 ). High structural similarities translate into comparable in vivo properties such as basolateral membrane localization in hepatocytes, Na + -dependent transport of bile acids or binding the viral preS1-domain of the HBV/HDV large surface proteins [ 9 , 13 , 18 , 19 , 20 ]. Moreover, a recent study focusing on functional and pharmacological comparison of hNTCP and mNtcp found strong correlation between the transport kinetics and inhibition pattern among both proteins [ 17 ].…”

Section: Ntcp: Structure and Transport Activitymentioning

confidence: 99%

Section: Ntcp: Structure and Transport Activitymentioning

confidence: 99%

“…NTCP is a membrane-localized protein, which is produced in the liver, where its unique expression defines its primary function [ 18 , 19 ]. In hepatocytes, NTCP acts as a transporter that is responsible for the sodium-dependent uptake of bile acids from the portal blood into hepatocytes through their sinusoidal/basolateral plasma membrane [ 18 , 19 ]. The list of bile acid molecules that are transported by NTCP is long and includes: cholic acid, chenodeoxycholic acid, deoxycholic acid, ursodeoxycholic acid, sarcosine cholic acid, glycocholic acid, glycochenodeoxycholic acid, glycodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid (TC), taurochenodeoxycholic acid (TCDC), taurodeoxycholic acid, tauroursodeoxycholic acid (TDC) and taurolithocholic acid (TLC) [ 27 ].…”

Section: Ntcp: Structure and Transport Activitymentioning

confidence: 99%

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Multitasking Na+/Taurocholate Cotransporting Polypeptide (NTCP) as a Drug Target for HBV Infection: From Protein Engineering to Drug Discovery

Zakrzewicz

Geyer

2022

Biomedicines

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Hepatitis B virus (HBV) infections are among the major public health concerns worldwide with more than 250 million of chronically ill individuals. Many of them are additionally infected with the Hepatitis D virus, a satellite virus to HBV. Chronic infection frequently leads to serious liver diseases including cirrhosis and hepatocellular carcinoma, the most common type of liver cancer. Although current antiviral therapies can control HBV replication and slow down disease progress, there is an unmet medical need to identify therapies to cure this chronic infectious disease. Lately, a noteworthy progress in fighting against HBV has been made by identification of the high-affinity hepatic host receptor for HBV and HDV, namely Na+/taurocholate cotransporting polypeptide (NTCP, gene symbol SLC10A1). Next to its primary function as hepatic uptake transporter for bile acids, NTCP is essential for the cellular entry of HBV and HDV into hepatocytes. Due to this high-ranking discovery, NTCP has become a valuable target for drug development strategies for HBV/HDV-infected patients. In this review, we will focus on a newly predicted three-dimensional NTCP model that was generated using computational approaches and discuss its value in understanding the NTCP’s membrane topology, substrate and virus binding taking place in plasma membranes. We will review existing data on structural, functional, and biological consequences of amino acid residue changes and mutations that lead to loss of NTCP’s transport and virus receptor functions. Finally, we will discuss new directions for future investigations aiming at development of new NTCP-based HBV entry blockers that inhibit HBV tropism in human hepatocytes.

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L‐Theanine regulates lipid metabolism by modulating gut microbiota and bile acid metabolism

Kong

Zhang

et al. 2022

J Sci Food Agric

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BACKGROUND: L-Theanine (LTA) is a biologically active ingredient in tea that shows great potential for regulating lipid metabolism. Bile acids (BA), an important end-product of cholesterol catabolism, participate in the regulation of lipid metabolism and gut microbiota. Here, we investigated the effect of LTA on lipid metabolism and the mechanism by which it regulates BA metabolism and gut microbiota. Male BALB/c mice were treated with LTA for 28 days.RESULTS: Daily LTA doses of 100 and 300 mg kg −1 d −1 altered the gut microbiota in mice, predominantly by decreasing Lactobacillus, Streptococcus, Bacteroides, Clostridium and Enterorhabdus microbes associated with bile-salt hydrolase (BSH) activity, thereby decreasing the activity of BSH and increasing the levels of ileum conjugated BA (such as glycocholic acid (GCA) and lithocholic acid), thereby inhibiting the intestinal farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) signaling pathway. Inhibition of FXR-FGF15 signaling was accompanied by upregulation of cholesterol 7⊍-hydroxylase (CYP7A1) mRNA and protein expression and increased hepatic production of cholic acid, deoxycholic acid, GCA, glycine cholic acid and glycine ursodeoxycholic acid. Meanwhile, increasing hepatic unconjugated BA upregulated the mRNA and protein expression of liver 3-hydroxy-3-methylglutaryl-CoA reductase and downregulated the mRNA and protein expression of stearoyl-CoA desaturase-1, liver low-density lipoprotein receptor and type B scavenger receptor. Therefore, the serum levels of cholesterol and triglycerides decreased. CONCLUSION: Our findings indicate that LTA regulates lipid metabolism by modulating the gut microbiota and BA metabolism via the FXR-FGF15-CYP7A1 pathway.

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Molecular regulation of the hepatic bile acid uptake transporter and HBV entry receptor NTCP

Cited by 23 publications

References 88 publications

Ilexsaponin A1 Ameliorates Diet-Induced Nonalcoholic Fatty Liver Disease by Regulating Bile Acid Metabolism in Mice

Ilexsaponin A1 Ameliorates Diet-Induced Nonalcoholic Fatty Liver Disease by Regulating Bile Acid Metabolism in Mice

Multitasking Na+/Taurocholate Cotransporting Polypeptide (NTCP) as a Drug Target for HBV Infection: From Protein Engineering to Drug Discovery

L‐Theanine regulates lipid metabolism by modulating gut microbiota and bile acid metabolism

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