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Fructose Induced KHK-C Increases ER Stress and Modulates Hepatic Transcriptome to Drive Liver Disease in Diet-Induced and Genetic Models of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome, and is estimated to affect one billion individuals worldwide. An increased intake of a high-fat diet (HFD) and sugar-sweetened beverages are risk-factors for NAFLD development, but how their combined intake pro...

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Autores principales: Park, Se-Hyung, Helsley, Robert N., Fadhul, Taghreed, Willoughby, Jennifer L.S., Noetzli, Leila, Tu, Ho-Chou, Solheim, Marie H., Fujisaka, Shiho, Pan, Hui, Dreyfuss, Jonathan M., Bons, Joanna, Rose, Jacob, King, Christina D., Schilling, Birgit, Lusis, Aldons J., Pan, Calvin, Gupta, Manoj, Kulkarni, Rohit N., Fitzgerald, Kevin, Kern, Philip A., Divanovic, Senad, Kahn, C. Ronald, Softic, Samir
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9900898/
https://www.ncbi.nlm.nih.gov/pubmed/36747758
http://dx.doi.org/10.1101/2023.01.27.525605
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author Park, Se-Hyung
Helsley, Robert N.
Fadhul, Taghreed
Willoughby, Jennifer L.S.
Noetzli, Leila
Tu, Ho-Chou
Solheim, Marie H.
Fujisaka, Shiho
Pan, Hui
Dreyfuss, Jonathan M.
Bons, Joanna
Rose, Jacob
King, Christina D.
Schilling, Birgit
Lusis, Aldons J.
Pan, Calvin
Gupta, Manoj
Kulkarni, Rohit N.
Fitzgerald, Kevin
Kern, Philip A.
Divanovic, Senad
Kahn, C. Ronald
Softic, Samir
author_facet Park, Se-Hyung
Helsley, Robert N.
Fadhul, Taghreed
Willoughby, Jennifer L.S.
Noetzli, Leila
Tu, Ho-Chou
Solheim, Marie H.
Fujisaka, Shiho
Pan, Hui
Dreyfuss, Jonathan M.
Bons, Joanna
Rose, Jacob
King, Christina D.
Schilling, Birgit
Lusis, Aldons J.
Pan, Calvin
Gupta, Manoj
Kulkarni, Rohit N.
Fitzgerald, Kevin
Kern, Philip A.
Divanovic, Senad
Kahn, C. Ronald
Softic, Samir
author_sort Park, Se-Hyung
collection PubMed
description Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome, and is estimated to affect one billion individuals worldwide. An increased intake of a high-fat diet (HFD) and sugar-sweetened beverages are risk-factors for NAFLD development, but how their combined intake promotes progression to a more severe form of liver injury is unknown. Here we show that fructose metabolism via ketohexokinase (KHK) C isoform increases endoplasmic reticulum (ER) stress in a dose dependent fashion, so when fructose is coupled with a HFD intake it leads to unresolved ER stress. Conversely, a liver-specific knockdown of KHK in C57BL/6J male mice consuming fructose on a HFD is adequate to improve the NAFLD activity score and exert a profound effect on the hepatic transcriptome. Overexpression of KHK-C in cultured hepatocytes is sufficient to induce ER stress in fructose free media. Upregulation of KHK-C is also observed in genetically obesity ob/ob, db/db and lipodystrophic FIRKO male mice, whereas KHK knockdown in these mice improves metabolic function. Additionally, in over 100 inbred strains of male or female mice hepatic KHK expression correlates positively with adiposity, insulin resistance, and liver triglycerides. Similarly, in 241 human subjects and their controls, hepatic Khk expression is upregulated in early, but not late stages of NAFLD. In summary, we describe a novel role of KHK-C in triggering ER stress, which offers a mechanistic understanding of how the combined intake of fructose and a HFD propagates the development of metabolic complications.
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spelling pubmed-99008982023-02-07 Fructose Induced KHK-C Increases ER Stress and Modulates Hepatic Transcriptome to Drive Liver Disease in Diet-Induced and Genetic Models of NAFLD. Park, Se-Hyung Helsley, Robert N. Fadhul, Taghreed Willoughby, Jennifer L.S. Noetzli, Leila Tu, Ho-Chou Solheim, Marie H. Fujisaka, Shiho Pan, Hui Dreyfuss, Jonathan M. Bons, Joanna Rose, Jacob King, Christina D. Schilling, Birgit Lusis, Aldons J. Pan, Calvin Gupta, Manoj Kulkarni, Rohit N. Fitzgerald, Kevin Kern, Philip A. Divanovic, Senad Kahn, C. Ronald Softic, Samir bioRxiv Article Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome, and is estimated to affect one billion individuals worldwide. An increased intake of a high-fat diet (HFD) and sugar-sweetened beverages are risk-factors for NAFLD development, but how their combined intake promotes progression to a more severe form of liver injury is unknown. Here we show that fructose metabolism via ketohexokinase (KHK) C isoform increases endoplasmic reticulum (ER) stress in a dose dependent fashion, so when fructose is coupled with a HFD intake it leads to unresolved ER stress. Conversely, a liver-specific knockdown of KHK in C57BL/6J male mice consuming fructose on a HFD is adequate to improve the NAFLD activity score and exert a profound effect on the hepatic transcriptome. Overexpression of KHK-C in cultured hepatocytes is sufficient to induce ER stress in fructose free media. Upregulation of KHK-C is also observed in genetically obesity ob/ob, db/db and lipodystrophic FIRKO male mice, whereas KHK knockdown in these mice improves metabolic function. Additionally, in over 100 inbred strains of male or female mice hepatic KHK expression correlates positively with adiposity, insulin resistance, and liver triglycerides. Similarly, in 241 human subjects and their controls, hepatic Khk expression is upregulated in early, but not late stages of NAFLD. In summary, we describe a novel role of KHK-C in triggering ER stress, which offers a mechanistic understanding of how the combined intake of fructose and a HFD propagates the development of metabolic complications. Cold Spring Harbor Laboratory 2023-01-27 /pmc/articles/PMC9900898/ /pubmed/36747758 http://dx.doi.org/10.1101/2023.01.27.525605 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Park, Se-Hyung
Helsley, Robert N.
Fadhul, Taghreed
Willoughby, Jennifer L.S.
Noetzli, Leila
Tu, Ho-Chou
Solheim, Marie H.
Fujisaka, Shiho
Pan, Hui
Dreyfuss, Jonathan M.
Bons, Joanna
Rose, Jacob
King, Christina D.
Schilling, Birgit
Lusis, Aldons J.
Pan, Calvin
Gupta, Manoj
Kulkarni, Rohit N.
Fitzgerald, Kevin
Kern, Philip A.
Divanovic, Senad
Kahn, C. Ronald
Softic, Samir
Fructose Induced KHK-C Increases ER Stress and Modulates Hepatic Transcriptome to Drive Liver Disease in Diet-Induced and Genetic Models of NAFLD.
title Fructose Induced KHK-C Increases ER Stress and Modulates Hepatic Transcriptome to Drive Liver Disease in Diet-Induced and Genetic Models of NAFLD.
title_full Fructose Induced KHK-C Increases ER Stress and Modulates Hepatic Transcriptome to Drive Liver Disease in Diet-Induced and Genetic Models of NAFLD.
title_fullStr Fructose Induced KHK-C Increases ER Stress and Modulates Hepatic Transcriptome to Drive Liver Disease in Diet-Induced and Genetic Models of NAFLD.
title_full_unstemmed Fructose Induced KHK-C Increases ER Stress and Modulates Hepatic Transcriptome to Drive Liver Disease in Diet-Induced and Genetic Models of NAFLD.
title_short Fructose Induced KHK-C Increases ER Stress and Modulates Hepatic Transcriptome to Drive Liver Disease in Diet-Induced and Genetic Models of NAFLD.
title_sort fructose induced khk-c increases er stress and modulates hepatic transcriptome to drive liver disease in diet-induced and genetic models of nafld.
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9900898/
https://www.ncbi.nlm.nih.gov/pubmed/36747758
http://dx.doi.org/10.1101/2023.01.27.525605
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