Cover Image

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

Show other versions (1)

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 a...

Full description

Saved in:
Bibliographic Details
Main Authors: Gallage, Suchira (Author) , Ali, Sheikh Adnan (Author) , Barragan Avila, José Efren (Author) , Seymen, Nogayhan (Author) , Ramadori, Pierluigi (Author) , Joerke, Vera (Author) , Zizmare, Laimdota (Author) , Aicher, David (Author) , Gopalsamy, Indresh K. (Author) , Fong, Winnie (Author) , Kosla, Jan (Author) , Focaccia, Enrico (Author) , Li, Xin (Author) , Yousuf, Suhail (Author) , Sijmonsma, Tjeerd (Author) , Rahbari, Mohammad (Author) , Kommoss, Katharina (Author) , Billeter, Adrian (Author) , Prokosch, Sandra (Author) , Rothermel, Ulrike (Author) , Mueller, Florian (Author) , Hetzer, Jenny (Author) , Heide, Danijela (Author) , Schinkel, Benjamin (Author) , Machauer, Tim (Author) , Pichler, Bernd (Author) , Malek, Nisar Peter (Author) , Longerich, Thomas (Author) , Roth, Susanne (Author) , Rose, Adam J. (Author) , Schwenck, Johannes (Author) , Trautwein, Christoph (Author) , Karimi, Mohammad M. (Author) , Heikenwälder, Mathias (Author)
Format: Article (Journal)
Language:English
Published: 4 June 2024
In: Cell metabolism
Year: 2024, Volume: 36, Issue: 6, Pages: 1371-1393.e7
ISSN:1932-7420
DOI:10.1016/j.cmet.2024.04.015
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.cmet.2024.04.015
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S1550413124001359
Get full text
Author Notes:Suchira Gallage, Adnan Ali, Jose Efren Barragan Avila, Nogayhan Seymen, Pierluigi Ramadori, Vera Joerke, Laimdota Zizmare, David Aicher, Indresh K. Gopalsamy, Winnie Fong, Jan Kosla, Enrico Focaccia, Xin Li, Suhail Yousuf, Tjeerd Sijmonsma, Mohammad Rahbari, Katharina S. Kommoss, Adrian Billeter, Sandra Prokosch, Ulrike Rothermel, Florian Mueller, Jenny Hetzer, Danijela Heide, Benjamin Schinkel, Tim Machauer, Bernd Pichler, Nisar P. Malek, Thomas Longerich, Susanne Roth, Adam J. Rose, Johannes Schwenck, Christoph Trautwein, Mohammad M. Karimi, and Mathias Heikenwalder
Description
Summary: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.
Item Description:Online verfügbar: 7. Mai 2024, Artikelversion: 4. Juni 2024
Gesehen am 27.11.2024
Physical Description:Online Resource
ISSN:1932-7420
DOI:10.1016/j.cmet.2024.04.015

Similar Items