Funded in part by Bristol-Myers Squibb, Boehringer Ingelheim, Werner Siemens-Stiftung
A 5:2 intermittent fasting regimen ameliorates NASH and fibrosis and blunts HCC development via hepatic PPARα and PCK1
Gallage S, Ali A, Barragan Avila JE, Seymen N, Ramadori P, Joerke V, Zizmare L, Aicher D, Gopalsamy IK, Fong W, Kosla J, Focaccia E, Li X, Yousuf S, Sijmonsma T, Rahbari M, Kommoss KS, Billeter A, Prokosch S, Rothermel U, Mueller F, Hetzer J, Heide D, Schinkel B, Machauer T, Pichler B, Malek NP, Longerich T, Roth S, Rose AJ, Schwenck J, Trautwein C, Karimi MM, Heikenwalder M
Cell metabolism · 98 citations
Review labels
Neutral facts our review recorded about how this study was done. They describe method, never whether we like the result.
How it was studied
- Design
- Animal study (classified by our AI screen)
- Studied in
- People, plus animal or lab work
- Main outcome
- Clinical events such as disease or death
Who paid for it
- Funding
- Industry funded
- Company
- Bristol-Myers Squibb
- Company
- Boehringer Ingelheim
- University or hospital
- Deutsches Krebsforschungszentrum
- Company
- Werner Siemens-Stiftung
- Government
- European Commission
- Government
- Deutsche Forschungsgemeinschaft
- University or hospital
- Universität Heidelberg
- Government
- Fonds Wetenschappelijk Onderzoek
- Nonprofit
- Deutsche Krebshilfe
- Nonprofit
- Dieter Morszeck Stiftung
- Government
- European Research Council
- University or hospital
- German Cancer Research Centre
- Grants
- Deutsche Krebshilfe (70112720); Fonds Wetenschappelijk Onderzoek (30826052); Deutsche Forschungsgemeinschaft (390900677)
Based on 12 listed funder(s).
Publication
- Published
- 2024-05-07 · Cell Metab · vol. 36 · issue 6 · pp. 1371–1393.e7
- Publisher
- Cell Press
- Cited
- 114 citations · more than 100% of similar papers · 29.8× the field average
- Impact
- Top 10% most cited in its field
- References
- 67 works
- Access
- Open access (hybrid journal) · CC-BY
- Research areas
- Liver Disease Diagnosis and Treatment · Dietary Effects on Health · Diet and metabolism studies
- Keywords
- Steatohepatitis, Endocrinology, Fatty liver, Internal medicine, Steatosis, Glucocorticoid receptor, Fibrosis, Nuclear receptor, Peroxisome proliferator-activated receptor, Biology, Medicine, Receptor, Glucocorticoid, Biochemistry
- MeSH
- liver, animals, mice, inbred c57bl, humans, mice, carcinoma, hepatocellular, liver neoplasms, liver cirrhosis, phosphoenolpyruvate carboxykinase (gtp), intracellular signaling peptides and proteins, ppar alpha, fasting, signal transduction, male, non-alcoholic fatty liver disease, intermittent fasting
34 authors
From DE, GB, US
- Suchira Gallage · correspondingGerman Cancer Research Center; Heidelberg University
- Adnan AliGerman Cancer Research Center; Heidelberg University
- Jose Efren Barragan AvilaGerman Cancer Research Center; Heidelberg University
- Nogayhan SeymenKing's College London
- Pierluigi RamadoriGerman Cancer Research Center; Heidelberg University
- Vera JoerkeSiemens (Germany); University of Tübingen
Abstract
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.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY).
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