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ACLY as a modulator of liver cell functions and its role in Metabolic Dysfunction-Associated Steatohepatitis
BACKGROUND: Non-alcoholic Fatty Liver Disease (NAFLD), now better known as Metabolic (Dysfunction)-Associated Fatty Liver Disease (MAFLD) and its progression to Nonalcoholic Steatohepatitis (NASH), more recently referred to as Metabolic (Dysfunction)-Associated Steatohepatitis (MASH) are the most co...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10463545/ https://www.ncbi.nlm.nih.gov/pubmed/37620891 http://dx.doi.org/10.1186/s12967-023-04431-w |
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author | Convertini, Paolo Santarsiero, Anna Todisco, Simona Gilio, Michele Palazzo, Donatella Pappalardo, Ilaria Iacobazzi, Dominga Frontuto, Maria Infantino, Vittoria |
author_facet | Convertini, Paolo Santarsiero, Anna Todisco, Simona Gilio, Michele Palazzo, Donatella Pappalardo, Ilaria Iacobazzi, Dominga Frontuto, Maria Infantino, Vittoria |
author_sort | Convertini, Paolo |
collection | PubMed |
description | BACKGROUND: Non-alcoholic Fatty Liver Disease (NAFLD), now better known as Metabolic (Dysfunction)-Associated Fatty Liver Disease (MAFLD) and its progression to Nonalcoholic Steatohepatitis (NASH), more recently referred to as Metabolic (Dysfunction)-Associated Steatohepatitis (MASH) are the most common causes of liver failure and chronic liver damage. The new names emphasize the metabolic involvement both in relation to liver function and pathological features with extrahepatic manifestations. This study aims to explore the role of the immunometabolic enzyme ATP citrate lyase (ACLY), with a critical function in lipogenesis, carbohydrate metabolism, gene expression and inflammation. METHODS: ACLY function was investigated in TNFα-triggered human hepatocytes and in PBMC-derived macrophages from MASH patients. Evaluation of expression levels was carried out by western blotting and/or RT-qPCR. In the presence or absence of ACLY inhibitors, ROS, lipid peroxidation and GSSG oxidative stress biomarkers were quantified. Chromatin immunoprecipitation (ChIP), transient transfections, immunocytochemistry, histone acetylation quantitation were used to investigate ACLY function in gene expression reprogramming. IL-6 and IL-1β were quantified by Lumit immunoassays. RESULTS: Mechanistically, ACLY inhibition reverted lipid accumulation and oxidative damage while reduced secretion of inflammatory cytokines in TNFα-triggered human hepatocytes. These effects impacted not only on lipid metabolism but also on other crucial features of liver function such as redox status and production of inflammatory mediators. Moreover, ACLY mRNA levels together with those of malic enzyme 1 (ME1) increased in human PBMC-derived macrophages from MASH patients when compared to age-matched healthy controls. Remarkably, a combination of hydroxycitrate (HCA), the natural ACLY inhibitor, with red wine powder (RWP) significantly lowered ACLY and ME1 mRNA amount as well as IL-6 and IL-1β production in macrophages from subjects with MASH. CONCLUSION: Collectively, our findings for the first time highlight a broad spectrum of ACLY functions in liver as well as in the pathogenesis of MASH and its diagnostic and therapeutic potential value. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04431-w. |
format | Online Article Text |
id | pubmed-10463545 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-104635452023-08-30 ACLY as a modulator of liver cell functions and its role in Metabolic Dysfunction-Associated Steatohepatitis Convertini, Paolo Santarsiero, Anna Todisco, Simona Gilio, Michele Palazzo, Donatella Pappalardo, Ilaria Iacobazzi, Dominga Frontuto, Maria Infantino, Vittoria J Transl Med Research BACKGROUND: Non-alcoholic Fatty Liver Disease (NAFLD), now better known as Metabolic (Dysfunction)-Associated Fatty Liver Disease (MAFLD) and its progression to Nonalcoholic Steatohepatitis (NASH), more recently referred to as Metabolic (Dysfunction)-Associated Steatohepatitis (MASH) are the most common causes of liver failure and chronic liver damage. The new names emphasize the metabolic involvement both in relation to liver function and pathological features with extrahepatic manifestations. This study aims to explore the role of the immunometabolic enzyme ATP citrate lyase (ACLY), with a critical function in lipogenesis, carbohydrate metabolism, gene expression and inflammation. METHODS: ACLY function was investigated in TNFα-triggered human hepatocytes and in PBMC-derived macrophages from MASH patients. Evaluation of expression levels was carried out by western blotting and/or RT-qPCR. In the presence or absence of ACLY inhibitors, ROS, lipid peroxidation and GSSG oxidative stress biomarkers were quantified. Chromatin immunoprecipitation (ChIP), transient transfections, immunocytochemistry, histone acetylation quantitation were used to investigate ACLY function in gene expression reprogramming. IL-6 and IL-1β were quantified by Lumit immunoassays. RESULTS: Mechanistically, ACLY inhibition reverted lipid accumulation and oxidative damage while reduced secretion of inflammatory cytokines in TNFα-triggered human hepatocytes. These effects impacted not only on lipid metabolism but also on other crucial features of liver function such as redox status and production of inflammatory mediators. Moreover, ACLY mRNA levels together with those of malic enzyme 1 (ME1) increased in human PBMC-derived macrophages from MASH patients when compared to age-matched healthy controls. Remarkably, a combination of hydroxycitrate (HCA), the natural ACLY inhibitor, with red wine powder (RWP) significantly lowered ACLY and ME1 mRNA amount as well as IL-6 and IL-1β production in macrophages from subjects with MASH. CONCLUSION: Collectively, our findings for the first time highlight a broad spectrum of ACLY functions in liver as well as in the pathogenesis of MASH and its diagnostic and therapeutic potential value. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04431-w. BioMed Central 2023-08-24 /pmc/articles/PMC10463545/ /pubmed/37620891 http://dx.doi.org/10.1186/s12967-023-04431-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Convertini, Paolo Santarsiero, Anna Todisco, Simona Gilio, Michele Palazzo, Donatella Pappalardo, Ilaria Iacobazzi, Dominga Frontuto, Maria Infantino, Vittoria ACLY as a modulator of liver cell functions and its role in Metabolic Dysfunction-Associated Steatohepatitis |
title | ACLY as a modulator of liver cell functions and its role in Metabolic Dysfunction-Associated Steatohepatitis |
title_full | ACLY as a modulator of liver cell functions and its role in Metabolic Dysfunction-Associated Steatohepatitis |
title_fullStr | ACLY as a modulator of liver cell functions and its role in Metabolic Dysfunction-Associated Steatohepatitis |
title_full_unstemmed | ACLY as a modulator of liver cell functions and its role in Metabolic Dysfunction-Associated Steatohepatitis |
title_short | ACLY as a modulator of liver cell functions and its role in Metabolic Dysfunction-Associated Steatohepatitis |
title_sort | acly as a modulator of liver cell functions and its role in metabolic dysfunction-associated steatohepatitis |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10463545/ https://www.ncbi.nlm.nih.gov/pubmed/37620891 http://dx.doi.org/10.1186/s12967-023-04431-w |
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