Details

Autor(en) / Beteiligte

• Gallage, Suchira
• Ali, Adnan
• Barragan Avila, Jose Efren
• Seymen, Nogayhan
• Ramadori, Pierluigi
• Joerke, Vera
• Zizmare, Laimdota
• Aicher, David
• Gopalsamy, Indresh K.
• Fong, Winnie
• Kosla, Jan
• Focaccia, Enrico
• Li, Xin
• Yousuf, Suhail
• Sijmonsma, Tjeerd
• Rahbari, Mohammad
• Kommoss, Katharina S.
• Billeter, Adrian
• Prokosch, Sandra
• Rothermel, Ulrike
• Mueller, Florian
• Hetzer, Jenny
• Heide, Danijela
• Schinkel, Benjamin
• Machauer, Tim
• Pichler, Bernd
• Malek, Nisar P.
• Longerich, Thomas
• Roth, Susanne
• Rose, Adam J.
• Schwenck, Johannes
• Trautwein, Christoph
• Karimi, Mohammad M.
• Heikenwalder, Mathias

Titel

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

Ist Teil von

• Cell metabolism, 2024-06, Vol.36 (6), p.1371-1393.e7

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2024

Quelle

Elsevier ScienceDirect Journals Complete

Beschreibungen/Notizen

• 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. [Display omitted] •IF 5:2 regimen prevents and ameliorates NASH and fibrosis and limits HCC development•Timing, length, and number of fasting cycles dictate the effectiveness of fasting•PPARα and PCK1 are hepatic executors of the beneficial effects of fasting in NASH•Pck1 overexpression lowers lipid accumulation and hepatic steatosis An intermittent fasting 5:2 regimen prevents and ameliorates NASH and fibrosis and limits HCC development in distinct diet-induced models of NASH and NASH-HCC. The timing, length, and number of fasting cycles dictate the effectiveness of fasting. PPARα and PCK1 are hepatic executors of the beneficial effects of fasting in NASH.