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Modeling PNPLA3-Associated NAFLD Using Human-Induced Pluripotent Stem Cells.

Samantha G Tilson^1,2,3, Carola M Morell², An-Sofie Lenaerts²

¹Wellcome Sanger Institute, Hinxton, United Kingdom.

Hepatology (Baltimore, Md.)

|July 21, 2021

Summary

This summary is machine-generated.

The patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M variant impairs liver function, increasing susceptibility to fatty liver disease (NAFLD) and toxins. This study models NAFLD using gene-edited stem cells to reveal PNPLA3's crucial role.

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Area of Science:

Hepatology
Genetics
Stem Cell Biology

Background:

Non-alcoholic fatty liver disease (NAFLD) is a significant health concern with incompletely understood pathogenesis.
Genetic factors, particularly the PNPLA3 I148M variant, are increasingly recognized for their role in NAFLD progression.
The precise mechanisms by which PNPLA3 variants influence NAFLD development remain largely unknown.

Purpose of the Study:

To investigate the functional mechanisms of PNPLA3 variants in NAFLD pathogenesis.
To develop and utilize an in vitro model of NAFLD using human-induced pluripotent stem cells (hiPSCs) and CRISPR/Cas9 gene editing.

Main Methods:

Generated isogenic hiPSC lines with PNPLA3 knockout (PNPLA3^KO) and the I148M variant (PNPLA3^I148M).
Differentiated hiPSCs into hepatocytes and induced NAFLD-like phenotypes using free fatty acids.
Characterized cells using functional, transcriptomic, and lipidomic assays.

Main Results:

PNPLA3^KO hepatocytes exhibited increased lipid accumulation and altered responses to lipid-induced stress.
Loss of PNPLA3 function reduced xenobiotic metabolism and increased susceptibility to ethanol and methotrexate toxicity.
PNPLA3^I148M cells displayed an intermediate phenotype between wild-type and PNPLA3^KO cells.

Conclusions:

The PNPLA3 I148M variant results in a loss of function.
This loss of function predisposes individuals to hepatic steatosis (fatty liver).
The variant also increases susceptibility to hepatotoxins, contributing to NAFLD pathogenesis.