From fatty hepatocytes to impaired bile flow: Matching model systems for liver biology and disease

Kunst, Roni F.; Niemeijer, Marije; Laan, Luc J. W. van der; Spee, Bart; Graaf, Stan F.J. van de

doi:10.1016/j.bcp.2020.114173

Cited by 8 publications

(3 citation statements)

References 216 publications

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“…In a similar manner, NTCP deficiency can increase plasma bile acid levels. Indeed, extremely high concentration of bile salts was measured in NTCP-deficient individuals, thereby manifesting in conjugated hypercholanemia with no apparent long-term clinical consequences [ 20 , 47 ]. Although the elevated bile acids in the blood circulation are well-tolerated, the metabolic effects related to their relatively high levels, for instance changes in CYP3A activity or release of glucagon-like 1 (GLP-1), have been reported [ 48 , 49 , 50 ].…”

Section: Ntcp: Structure and Transport Activitymentioning

confidence: 99%

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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Section: Ntcp: Structure and Transport Activitymentioning

confidence: 99%

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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“…The latter cannot be overlooked when attempting to determine the pathophysiology behind disease processes or response to medications. 17 18…”

Section: The 3d Organoid Modelmentioning

confidence: 99%

“…The latter cannot be overlooked when attempting to determine the pathophysiology behind disease processes or response to medications. 17,18 Furthermore, freshly isolated primary human hepatocytes have been noted to rapidly lose their function and ability to differentiate after only a few days in standard 2D monolayer culture, making it challenging to study long-term effects on liver function. 19 In contrast, it has been well-demonstrated that primary hepatocytes in organoids can maintain their function for at least 5 weeks, with proteomic analysis revealing that in vivo phenotypes are maintained in 3D organoids, while the 2D monolayer proteome underwent striking changes after only 24 hours.…”

Section: Characteristics and Key Benefitsmentioning

confidence: 99%

Three-Dimensional Organoids as a Model to Study Nonalcoholic Fatty Liver Disease

et al. 2022

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Despite the rising prevalence of nonalcoholic fatty liver disease (NAFLD), the underlying disease pathophysiology remains unclear. The need is great for an efficient and reliable ‘human’ in vitro model to study NAFLD and the progression to nonalcoholic steatohepatitis (NASH), which will soon become the leading indication for liver transplantation. Here, we review the recent developments in the use of 3D liver organoids as a model to study NAFLD and NASH pathophysiology and possible treatments. Various techniques that are currently used to make liver organoids are discussed, such as the use of induced pluripotent stem cells vs. primary cell lines and human vs. murine cells. Moreover, methods for inducing lipid droplet accumulation and fibrosis to model NAFLD are explored. Finally, the limitations specific to the 3D organoid model for NAFLD/NASH are reviewed, highlighting the need for further development of multilineage models to include hepatic nonparenchymal cells and immune cells. The ultimate goal is to be able to accurately recapitulate the complex liver microenvironment in which NAFLD develops and progresses to NASH.

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Methodology and Tools for Metallomics

Yan,

Xu,

Wang

2024

Applied Metallomics

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From fatty hepatocytes to impaired bile flow: Matching model systems for liver biology and disease

Cited by 8 publications

References 216 publications

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

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

Three-Dimensional Organoids as a Model to Study Nonalcoholic Fatty Liver Disease

Methodology and Tools for Metallomics

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