德国癌症研究中心Mathias Heikenwalder研究组报道，5:2间歇性禁食方案可通过肝脏PPARα和PCK1改善NASH和纤维化，并抑制HCC的发展。这一研究成果发表在2024年5月7日出版的国际学术期刊《细胞—代谢》上。

课题组研究人员发现，在不影响总热量摄入的情况下，间歇性禁食(IF) 5:2方案可以预防非酒精性脂肪性肝炎(NASH)的发展，并改善已建立的NASH和纤维化。

此外，IF 5:2方案在治疗性应用时可以减弱NASH-HCC (肝细胞癌)的转变。禁食周期的时间、长度和次数以及NASH饮食的类型是决定禁食益处的关键参数。结合蛋白质组学、转录组学和代谢组学分析发现，过氧化物酶体增殖物激活受体α (PPARα)和糖皮质激素信号诱导的PCK1共同作用，作为禁食反应的肝脏执行者。与此一致，PPARα靶点和PCK1在人类NASH中减少。值得注意的是，只有在小鼠活跃期开始的禁食才会诱导糖皮质激素信号传导，和游离脂肪酸诱导的PPARα信号传导。

然而，肝细胞特异性糖皮质激素受体缺失仅部分消除了肝脏禁食反应。相比之下，Ppara和Pck1在体内的联合敲低消除了禁食抗炎症和纤维化的有益结果。

此外，Pck1单独或与Ppara一起在体内过表达可降低肝脏甘油三酯和脂肪变性。他们的数据支持这样的观点，即间歇性禁食 5:2方案是一种有希望的干预NASH和随后的肝癌的方法。

据了解，间歇性禁食(IF)在非酒精性脂肪性肝炎(NASH)及其向肝细胞癌(HCC)转变中的作用和分子机制尚不清楚。

附：英文原文

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

Author: 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, Mathias Heikenwalder

Issue&Volume: 2024-05-07

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.

DOI: 10.1016/j.cmet.2024.04.015

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(24)00135-9