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Fatty Acid Excess Dysregulates CARF to Initiate the Development of Hepatic Steatosis

CARF (CDKN2AIP) regulates cellular fate in response to various stresses. However, its role in metabolic stress is unknown. We found that fatty livers from mice exhibit low CARF expression. Similarly, overloaded palmitate inhibited CARF expression in HepG2 cells, suggesting that excess fat-induced st...

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Autores principales: Hasan, Kamrul M., Parveen, Meher, Pena, Alondra, Bautista, Francisco, Rivera, Juan Carlos, Huerta, Roxana Ramirez, Martinez, Erica, Espinoza-Derout, Jorge, Sinha-Hikim, Amiya P., Friedman, Theodore C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093423/
https://www.ncbi.nlm.nih.gov/pubmed/37048142
http://dx.doi.org/10.3390/cells12071069
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author Hasan, Kamrul M.
Parveen, Meher
Pena, Alondra
Bautista, Francisco
Rivera, Juan Carlos
Huerta, Roxana Ramirez
Martinez, Erica
Espinoza-Derout, Jorge
Sinha-Hikim, Amiya P.
Friedman, Theodore C.
author_facet Hasan, Kamrul M.
Parveen, Meher
Pena, Alondra
Bautista, Francisco
Rivera, Juan Carlos
Huerta, Roxana Ramirez
Martinez, Erica
Espinoza-Derout, Jorge
Sinha-Hikim, Amiya P.
Friedman, Theodore C.
author_sort Hasan, Kamrul M.
collection PubMed
description CARF (CDKN2AIP) regulates cellular fate in response to various stresses. However, its role in metabolic stress is unknown. We found that fatty livers from mice exhibit low CARF expression. Similarly, overloaded palmitate inhibited CARF expression in HepG2 cells, suggesting that excess fat-induced stress downregulates hepatic CARF. In agreement with this, silencing and overexpressing CARF resulted in higher and lower fat accumulation in HepG2 cells, respectively. Furthermore, CARF overexpression lowered the ectopic palmitate accumulation in HepG2 cells. We were interested in understanding the role of hepatic CARF and underlying mechanisms in the development of NAFLD. Mechanistically, transcriptome analysis revealed that endoplasmic reticulum (ER) stress and oxidative stress pathway genes significantly altered in the absence of CARF. IRE1α, GRP78, and CHOP, markers of ER stress, were increased, and the treatment with TUDCA, an ER stress inhibitor, attenuated fat accumulation in CARF-deficient cells. Moreover, silencing CARF caused a reduction of GPX3 and TRXND3, leading to oxidative stress and apoptotic cell death. Intriguingly, CARF overexpression in HFD-fed mice significantly decreased hepatic steatosis. Furthermore, overexpression of CARF ameliorated the aberrant ER function and oxidative stress caused by fat accumulation. Our results further demonstrated that overexpression of CARF alleviates HFD-induced insulin resistance assessed with ITT and GTT assay. Altogether, we conclude that excess fat-induced reduction of CARF dysregulates ER functions and lipid metabolism leading to hepatic steatosis.
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spelling pubmed-100934232023-04-13 Fatty Acid Excess Dysregulates CARF to Initiate the Development of Hepatic Steatosis Hasan, Kamrul M. Parveen, Meher Pena, Alondra Bautista, Francisco Rivera, Juan Carlos Huerta, Roxana Ramirez Martinez, Erica Espinoza-Derout, Jorge Sinha-Hikim, Amiya P. Friedman, Theodore C. Cells Article CARF (CDKN2AIP) regulates cellular fate in response to various stresses. However, its role in metabolic stress is unknown. We found that fatty livers from mice exhibit low CARF expression. Similarly, overloaded palmitate inhibited CARF expression in HepG2 cells, suggesting that excess fat-induced stress downregulates hepatic CARF. In agreement with this, silencing and overexpressing CARF resulted in higher and lower fat accumulation in HepG2 cells, respectively. Furthermore, CARF overexpression lowered the ectopic palmitate accumulation in HepG2 cells. We were interested in understanding the role of hepatic CARF and underlying mechanisms in the development of NAFLD. Mechanistically, transcriptome analysis revealed that endoplasmic reticulum (ER) stress and oxidative stress pathway genes significantly altered in the absence of CARF. IRE1α, GRP78, and CHOP, markers of ER stress, were increased, and the treatment with TUDCA, an ER stress inhibitor, attenuated fat accumulation in CARF-deficient cells. Moreover, silencing CARF caused a reduction of GPX3 and TRXND3, leading to oxidative stress and apoptotic cell death. Intriguingly, CARF overexpression in HFD-fed mice significantly decreased hepatic steatosis. Furthermore, overexpression of CARF ameliorated the aberrant ER function and oxidative stress caused by fat accumulation. Our results further demonstrated that overexpression of CARF alleviates HFD-induced insulin resistance assessed with ITT and GTT assay. Altogether, we conclude that excess fat-induced reduction of CARF dysregulates ER functions and lipid metabolism leading to hepatic steatosis. MDPI 2023-04-01 /pmc/articles/PMC10093423/ /pubmed/37048142 http://dx.doi.org/10.3390/cells12071069 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hasan, Kamrul M.
Parveen, Meher
Pena, Alondra
Bautista, Francisco
Rivera, Juan Carlos
Huerta, Roxana Ramirez
Martinez, Erica
Espinoza-Derout, Jorge
Sinha-Hikim, Amiya P.
Friedman, Theodore C.
Fatty Acid Excess Dysregulates CARF to Initiate the Development of Hepatic Steatosis
title Fatty Acid Excess Dysregulates CARF to Initiate the Development of Hepatic Steatosis
title_full Fatty Acid Excess Dysregulates CARF to Initiate the Development of Hepatic Steatosis
title_fullStr Fatty Acid Excess Dysregulates CARF to Initiate the Development of Hepatic Steatosis
title_full_unstemmed Fatty Acid Excess Dysregulates CARF to Initiate the Development of Hepatic Steatosis
title_short Fatty Acid Excess Dysregulates CARF to Initiate the Development of Hepatic Steatosis
title_sort fatty acid excess dysregulates carf to initiate the development of hepatic steatosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093423/
https://www.ncbi.nlm.nih.gov/pubmed/37048142
http://dx.doi.org/10.3390/cells12071069
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