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

Suchira Gallage ¹, Adnan Ali ², Jose Efren Barragan Avila ²

¹German 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.
²German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
³Comprehensive Cancer Centre, School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, Denmark Hill, London, UK.
⁴Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Röntgenweg 13, 72076 Tübingen, Germany.
⁵Werner 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.
⁶University 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.
⁷Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany.
⁸German 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.
⁹German 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.
¹⁰Werner 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.
¹¹University 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.
¹²Institute of Pathology, Heidelberg University Hospital, Universitätsklinikum Heidelberg, Pathologisches Institut, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
¹³Nutrient 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.
¹⁴University 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.
¹⁵German 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.

⁰German 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.

Cell Metabolism +

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May 8, 2024

View abstract on PubMed

Summary

Intermittent fasting (IF) using a 5:2 diet prevents and treats non-alcoholic steatohepatitis (NASH) and liver cancer. Key molecular players include PPARα and PCK1, crucial for the liver

Area Of Science

Hepatology and metabolic disease research.
Molecular mechanisms of diet-induced liver changes.
Cancer prevention strategies.

Background

Non-alcoholic steatohepatitis (NASH) is a progressive liver disease.
NASH can advance to liver cancer (hepatocellular carcinoma, HCC).
The role of intermittent fasting (IF) in NASH and its progression to HCC is not well understood.

Purpose Of The Study

To investigate the efficacy of a 5:2 IF regimen in preventing and treating NASH.
To explore the molecular mechanisms underlying IF's effects on NASH and HCC.
To identify key molecular targets involved in the fasting response.

Main Methods

Utilized a 5:2 intermittent fasting (IF) regimen in a mouse model of NASH.
Performed proteomic, transcriptomic, and metabolomic analyses.
Investigated the roles of PPARα and PCK1 through genetic manipulation (knockdown and overexpression) and receptor deletion.

Main Results

The 5:2 IF regimen prevented and ameliorated established NASH and liver fibrosis without altering total calorie intake.
IF significantly blunted the transition from NASH to HCC.
PPARα and PCK1 were identified as key hepatic executors of the fasting response, with their combined action essential for IF's benefits.
Fasting initiated during the active phase robustly induced relevant signaling pathways.

Conclusions

The 5:2 IF regimen is a promising therapeutic strategy for NASH and preventing associated liver cancer.
PPARα and PCK1 signaling are critical molecular mediators of IF's protective effects in the liver.
Dietary interventions like IF warrant further investigation for metabolic liver diseases.

Keywords:

HCC IF MASH MASLD NAFLD NASH fasting intermittent fasting liver cancer

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