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 and abolished the beneficial outcomes of fasting against inflammation and fibrosis. Moreover, overexpression of alone or together with 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.

中文翻译：

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5:2 间歇性禁食方案可通过肝脏 PPARα 和 PCK1 改善 NASH 和纤维化，并减缓 HCC 的发展


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。在这里，我们发现 IF 5:2 方案可以预防 NASH 的发展，并改善已形成的 NASH 和纤维化，而不影响总热量摄入。此外，IF 5:2 方案在治疗应用时会减弱 NASH-HCC 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、转录组和代谢组分析发现，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 协同充当禁食反应的肝脏执行者。与此一致，人类 NASH 中 PPARα 靶标和 PCK1 减少。值得注意的是，只有在小鼠活跃期开始禁食才能强烈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，联合抑制和消除禁食对抗炎症和纤维化的有益结果。此外，单独或与肝甘油三酯降低和脂肪变性一起过度表达。我们的数据支持这样的观点，即 IF 5:2 方案是对抗 NASH 和随后的肝癌的一种有希望的干预措施。