PNPLA3-I148M genetic variant rewires lipid metabolism to drive programmed cell death in human hepatocytes.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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Florentino Rodrigo M, Animasahun Olamide, Haep Nils, Nenwani Minal, Omoloja Kehinde, Altay Leyla Nurcihan, Achreja Abhinav, Morita Kazutoyo, Motomura Takashi, Diaz-Aragon Ricardo, Faccioli Lanuza Ap, Sun Yiyue, Liu Zhenghao, Hu Zhiping, Yang Bo, Wuchu Fulei, Shankaran Ajay, Paserba Miya, Baratta Annalisa M, Arazov Shohrat, Kocas-Kilicarslan Zehra N, Meurs Noah, Behari Jaideep, Tafaleng Edgar N, Franks Jonathan, Ostrowska Alina, Tomiyama Takahiro, Yugawa Kyohei, Morinaga Akinari, Wang Zi, Takeishi Kazuki, Gavlock Dillon C, Miedel Mark, Taylor D Lansing, Fox Ira J, Yoshizumi Tomoharu, Nagrath Deepak, Soto-Gutierrez Alejandro
Аннотация
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.