Shanshan Liu, Yu Ji, Luyang Wei, Yiqiao Zhang, Linghang Zeng, Yiyang Min, Danyang Yin, Kun Liu, Chengjian Guan, Shumeng Liu, Huajing Yu, Zhongtao Zhang
Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
State Key Lab of Digestive Health, Beijing, China.
Nat Commun. 2025 Aug 26;16(1):7961. doi: 10.1038/s41467-025-62731-9.
Metabolic dysfunction-associated steatotic liver disease (MASLD), potentially ameliorated by bariatric-metabolic surgery, remains a global health concern in the absence of approved drugs. Protein post-translational modifications (PTMs) are crucial for MASLD. However, the functional significance of lysine crotonylation (Kcr) remains unclear. We aimed to investigate the mechanisms by Kcr-regulated IDH1 in the tricarboxylic acid (TCA) cycle and MASLD development. Herein, we reported a quantitative proteomics analysis of global crotonylome upon MASLD and Post-bariatric. Specifically, decreases in K58cr, K151cr, K212cr and K345cr of IDH1 upon MASLD were observed. PCAF and SIRT7 dynamically regulated the IDH1 Kcr. Abolishment of IDH1 Kcr impaired TCA cycle by decreasing IDH1 enzymatic activity. Male mice with liver-specific expression of crotonylation-mimic mutants of IDH1 were resistant to HFD-induced obesity, insulin resistance, glucose intolerance and MASLD. Our findings unravel the mechanisms of IDH1 Kcr and indicate that targeting PCAF/SIRT7-IDH1 Kcr and metabolites may be a promising strategy for MASLD therapy.
代谢功能障碍相关脂肪性肝病（MASLD）在缺乏获批药物的情况下仍是全球健康问题，尽管减肥代谢手术可能改善该病。蛋白质翻译后修饰（PTMs）对MASLD至关重要。然而，赖氨酸巴豆酰化（Kcr）的功能意义仍不清楚。我们旨在研究Kcr调节的异柠檬酸脱氢酶1（IDH1）在三羧酸（TCA）循环及MASLD发生发展中的机制。在此，我们报告了对MASLD及减肥代谢手术后整体巴豆酰化组的定量蛋白质组学分析。具体而言，观察到MASLD时IDH1的K58cr、K151cr、K212cr和K345cr减少。PCAF和SIRT7动态调节IDH1的Kcr。IDH1的Kcr缺失通过降低IDH1酶活性损害TCA循环。肝脏特异性表达IDH1巴豆酰化模拟突变体的雄性小鼠对高脂饮食诱导的肥胖、胰岛素抵抗、葡萄糖不耐受和MASLD具有抗性。我们的研究结果揭示了IDH1 Kcr的机制，并表明靶向PCAF/SIRT7-IDH1 Kcr和代谢物可能是治疗MASLD的一种有前景的策略。
