A 5:2 intermittent fasting regimen ameliorates NASH and fibrosis and blunts HCC development via hepatic PPARα and PCK1.

Autor:	Gallage S; German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; University Tuebingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Otfried-Müller-Straße 37, 72076 Tübingen. Electronic address: s.gallage@dkfz-heidelberg.de., Ali A; German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany., Barragan Avila JE; German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany., Seymen N; Comprehensive Cancer Centre, School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, Denmark Hill, London, UK., Ramadori P; German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; University Tuebingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Otfried-Müller-Straße 37, 72076 Tübingen., Joerke V; Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Röntgenweg 13, 72076 Tübingen, Germany., Zizmare L; Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Röntgenweg 13, 72076 Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies,' Eberhard-Karls University of Tübingen, Tübingen, Germany., Aicher D; University Tuebingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Otfried-Müller-Straße 37, 72076 Tübingen., Gopalsamy IK; University Tuebingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Otfried-Müller-Straße 37, 72076 Tübingen., Fong W; University Tuebingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Otfried-Müller-Straße 37, 72076 Tübingen., Kosla J; German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany., Focaccia E; German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany., Li X; German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany., Yousuf S; Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany., Sijmonsma T; German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany., Rahbari M; German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Department of Surgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Kommoss KS; German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany., Billeter A; Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany., Prokosch S; German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany., Rothermel U; German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany., Mueller F; German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany., Hetzer J; German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany., Heide D; German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany., Schinkel B; University Tuebingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Otfried-Müller-Straße 37, 72076 Tübingen., Machauer T; German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany., Pichler B; Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Röntgenweg 13, 72076 Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies,' Eberhard-Karls University of Tübingen, Tübingen, Germany; Department of Nuclear Medicine and Clinical Molecular Imaging, Eberhard-Karls University of Tübingen, Tübingen, Germany., Malek NP; University Tuebingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Otfried-Müller-Straße 37, 72076 Tübingen; Department Internal Medicine I, University Hospital Tübingen, Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies,' Eberhard-Karls University of Tübingen, Tübingen, Germany., Longerich T; Institute of Pathology, Heidelberg University Hospital, Universitätsklinikum Heidelberg, Pathologisches Institut, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany., Roth S; Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany., Rose AJ; Nutrient Metabolism and Signalling Laboratory, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, and Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia., Schwenck J; Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Röntgenweg 13, 72076 Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies,' Eberhard-Karls University of Tübingen, Tübingen, Germany; Department of Nuclear Medicine and Clinical Molecular Imaging, Eberhard-Karls University of Tübingen, Tübingen, Germany., Trautwein C; University Tuebingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Otfried-Müller-Straße 37, 72076 Tübingen; Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Röntgenweg 13, 72076 Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies,' Eberhard-Karls University of Tübingen, Tübingen, Germany., Karimi MM; Comprehensive Cancer Centre, School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, Denmark Hill, London, UK., Heikenwalder M; German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; University Tuebingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Otfried-Müller-Straße 37, 72076 Tübingen; Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies,' Eberhard-Karls University of Tübingen, Tübingen, Germany. Electronic address: m.heikenwaelder@dkfz-heidelberg.de.
Jazyk:	angličtina
Zdroj:	Cell metabolism [Cell Metab] 2024 Jun 04; Vol. 36 (6), pp. 1371-1393.e7. Date of Electronic Publication: 2024 May 07.
DOI:	10.1016/j.cmet.2024.04.015
Abstrakt:	The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen prevents NASH development as well as ameliorates established NASH and fibrosis without affecting total calorie intake. Furthermore, the IF 5:2 regimen blunted NASH-HCC transition when applied therapeutically. The timing, length, and number of fasting cycles as well as the type of NASH diet were critical parameters determining the benefits of fasting. Combined proteome, transcriptome, and metabolome analyses identified that peroxisome-proliferator-activated receptor alpha (PPARα) and glucocorticoid-signaling-induced PCK1 act co-operatively as hepatic executors of the fasting response. In line with this, PPARα targets and PCK1 were reduced in human NASH. Notably, only fasting initiated during the active phase of mice robustly induced glucocorticoid signaling and free-fatty-acid-induced PPARα signaling. However, hepatocyte-specific glucocorticoid receptor deletion only partially abrogated the hepatic fasting response. In contrast, the combined knockdown of Ppara and Pck1 in vivo abolished the beneficial outcomes of fasting against inflammation and fibrosis. Moreover, overexpression of Pck1 alone or together with Ppara in vivo lowered hepatic triglycerides and steatosis. Our data support the notion that the IF 5:2 regimen is a promising intervention against NASH and subsequent liver cancer. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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