PNPLA3-I148M genetic variant rewires lipid metabolism to drive programmed cell death in human hepatocytes

Genetic variants in lipid metabolism influence the risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD), cirrhosis, and end-stage liver disease (ESLD). The mechanisms by which these variants drive disease are poorly understood. Because of the PNPLA3-I148M variant's strong correlation with all stages of the MASLD spectrum and the lack of tractable therapeutic targets, we sought to understand its impact on cellular function and liver metabolism. Primary human hepatocytes (HAHs) and induced pluripotent stem cell-derived (iPSC-derived) hepatocytes (iHeps) from healthy individuals possessing the PNPLA3-I148M mutation were characterized for changes in lipid metabolism, cellular stress, and survival. Using lipidomics, metabolomics, stable isotope tracing, and flux propensity analysis, we created a comprehensive metabolic profile of the changes associated with the PNPLA3-I148M variant. Functional analysis showed that the presence of the PNPLA3-I148M variant increased endoplasmic reticulum stress, mitochondrial dysfunction, and peroxisomal β-oxidation, ultimately leading to cell death via ferroptosis. Nutritional interventions, ferroptosis-specific inhibitors, and genetic approaches modulating GPX4 activity in PNPLA3-I148M HAHs and iHeps decreased programmed cell death. Our findings indicate that therapies targeting ferroptosis in patients carrying the PNPLA3-I148M variant could affect the development of MASLD and ESLD and highlight the utility of iPSC-based models for the study of genetic contributions to hepatic disorders.

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Publication Details

Journal
JCI Insight
Published
2025-10-21
DOI
https://doi.org/10.1172/jci.insight.193805
Citations
2
Primary Topic
Liver Disease Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
2.71

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article

PNPLA3-I148M genetic variant rewires lipid metabolism to drive programmed cell death in human hepatocytes

Nils Haep, Jonathan Franks, Kazutoyo Morita, Minal Nenwani et al.
2 citations
JCI Insight
Liver Disease Diagnosis and Treatment
2.71
article

PNPLA3-I148M genetic variant rewires lipid metabolism to drive programmed cell death in human hepatocytes

Nils Haep, Jonathan Franks, Kazutoyo Morita, Minal Nenwani, Mark T. Miedel, Ricardo Díaz‐Aragon, Miya Paserba, Fulei Wuchu, Alejandro Soto–Gutiérrez, Lanuza A. P. Faccioli, Tomoharu Yoshizumi, Zi Wang, Deepak Nagrath, Ajay Shankaran, Shohrat Arazov, Alina Ostrowska, Kazuki Takeishi, Annalisa M. Baratta, Dillon Gavlock, Jaideep Behari, Abhinav Achreja, Takahiro Tomiyama, Edgar N. Tafaleng, Zehra N. Kocas‐Kilicarslan, Bo Yang, Olamide Animasahun, Ira J. Fox, Akinari Morinaga, Noah Meurs, Takashi Motomura, D. Lansing Taylor, Kyohei Yugawa, Leyla Nurcihan Altay, Yiyue Sun, Zhiping Hu, Rodrigo M. Florentino, Kehinde Omoloja, Zhenghao Liu
article en
2 citations

Abstract

Genetic variants in lipid metabolism influence the risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD), cirrhosis, and end-stage liver disease (ESLD). The mechanisms by which these variants drive disease are poorly understood. Because of the PNPLA3-I148M variant's strong correlation with all stages of the MASLD spectrum and the lack of tractable therapeutic targets, we sought to understand its impact on cellular function and liver metabolism. Primary human hepatocytes (HAHs) and induced pluripotent stem cell-derived (iPSC-derived) hepatocytes (iHeps) from healthy individuals possessing the PNPLA3-I148M mutation were characterized for changes in lipid metabolism, cellular stress, and survival. Using lipidomics, metabolomics, stable isotope tracing, and flux propensity analysis, we created a comprehensive metabolic profile of the changes associated with the PNPLA3-I148M variant. Functional analysis showed that the presence of the PNPLA3-I148M variant increased endoplasmic reticulum stress, mitochondrial dysfunction, and peroxisomal β-oxidation, ultimately leading to cell death via ferroptosis. Nutritional interventions, ferroptosis-specific inhibitors, and genetic approaches modulating GPX4 activity in PNPLA3-I148M HAHs and iHeps decreased programmed cell death. Our findings indicate that therapies targeting ferroptosis in patients carrying the PNPLA3-I148M variant could affect the development of MASLD and ESLD and highlight the utility of iPSC-based models for the study of genetic contributions to hepatic disorders.

JCI InsightVol. 10(23)
Kyushu University (JP), University of Pittsburgh (US), University of Michigan (US), Discovery Institute (US), Children's Hospital of Pittsburgh (US), University of Pittsburgh Medical Center (US), BioSurfaces (United States) (US), Transneft (Russia) (RU), Center for Systems Biology (US)
University of Pittsburgh, National Institutes of Health, Japan Society for the Promotion of Science
Openalex Percentile: Top 8%
Liver Disease Diagnosis and Treatment
2.71
DOIOpen Access PDFOpenAlex
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