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Effect of Hepatic Disease on Pharmacokinetics: Pathophysiologic Assessment and Liver Function Test01:22

Effect of Hepatic Disease on Pharmacokinetics: Pathophysiologic Assessment and Liver Function Test

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In clinical practice, the direct measurement of hepatic blood flow to evaluate liver function presents significant challenges due to the intricate and specialized nature of the necessary techniques. Consequently, healthcare professionals often rely on empirical estimates derived from thorough patient examinations and liver function tests to gauge liver health. Among the tools at their disposal, the Child–Pugh and MELD scoring systems stand out for their ability to categorize and assess...
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  1. Home
  3. Comparison Of Wild-type And High-risk Pnpla3 Variants In A Human Biomimetic Liver Microphysiology System For Metabolic Dysfunction-associated Steatotic Liver Disease Precision Therapy.
  1. Home
  3. Comparison Of Wild-type And High-risk Pnpla3 Variants In A Human Biomimetic Liver Microphysiology System For Metabolic Dysfunction-associated Steatotic Liver Disease Precision Therapy.

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Comparison of wild-type and high-risk PNPLA3 variants in a human biomimetic liver microphysiology system for

Mengying Xia1, Mahboubeh Varmazyad1, Iris Pla-Palacín1

  • 1Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, United States.

Frontiers in Cell and Developmental Biology
|September 26, 2024

View abstract on PubMed

Summary
This summary is machine-generated.
Keywords:
metabolic dysfunction-associated steatotic liver diseasemicrophysiology systemspatatin-like phospholipase domain-containing protein 3precision medicinereproducibility

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This study developed a liver acinus microphysiology system (LAMPS) using patient cells to model metabolic dysfunction-associated steatotic liver disease (MASLD). The system accurately reflects disease progression and drug response, paving the way for precision therapeutics.

Area of Science:

  • Hepatology and Metabolic Disease Research
  • Biomimetic Modeling and Precision Medicine
  • Drug Development and Clinical Trial Optimization

Background:

  • Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global epidemic affecting 30% of the population.
  • MASLD pathogenesis is complex, involving genetic, lifestyle, and environmental factors, leading to patient heterogeneity.
  • Current preclinical models fail to fully replicate MASLD complexity, hindering therapeutic development.

Purpose of the Study:

  • To develop a precision medicine strategy for MASLD using a liver acinus microphysiology system (LAMPS) with patient-derived cells.
  • To investigate the impact of the PNPLA3 rs738409 (I148M) genetic variant on MASLD progression within the LAMPS.
  • To evaluate the efficacy of resmetirom in the LAMPS under varying metabolic conditions.

Main Methods:

  • Constructed LAMPS using genotyped wild-type and PNPLA3 variant primary hepatocytes and non-parenchymal cells.
  • Mimicked normal fasting (NF), early metabolic syndrome (EMS), and late metabolic syndrome (LMS) conditions by altering media components.
  • Assessed model reproducibility and investigated resmetirom treatment response in different LAMPS configurations.

Main Results:

  • The PNPLA3 GG variant LAMPS showed increased steatosis, immune and stellate cell activation, and pro-fibrotic marker secretion compared to the wild-type CC LAMPS.
  • Resmetirom demonstrated greater efficacy in the wild-type CC LAMPS compared to the GG variant across multiple MASLD metrics.
  • The LAMPS platform proved reproducible and capable of reflecting MASLD progression and therapeutic response.

Conclusions:

  • The LAMPS platform is a valuable tool for developing MASLD precision therapeutics.
  • This model can aid in enriching patient cohorts for clinical trials and optimizing treatment strategies for specific patient subgroups.
  • The study provides a benchmark for future
  • patient biomimetic twins
  • using iPSC-derived liver cells.