Zhang Ranran, Liu Meitong, Lu Jing, Lu Shujing, Wang Yuanmeng, Guan Shuang
College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China.
State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, China.
J Agric Food Chem. 2024 Dec 4;72(48):26884-26897. doi: 10.1021/acs.jafc.4c06487. Epub 2024 Nov 20.
High fat diet (HFD) induces the enlargement and accumulation of lipid droplets (LDs) in hepatocytes, thereby influencing the homeostasis of lipid metabolism. Cell death-inducing DNA fragmentation factor-α-like effector C (CIDEC), a surface protein of LDs, facilitates their fusion and growth, transforming small LDs into larger ones. Lipophagy, a selective form of autophagy, primarily targets small LDs for degradation. Fisetin (FIS), a natural dietary flavonoid present in various fruits and vegetables, has an unclear mechanism for reducing LD accumulation. In this study, we observed that FIS significantly ameliorated HFD-induced lipid accumulation in the hepatocytes of C57BL/6 mice. In further mechanistic studies, we revealed that FFA enhanced the expression of CIDEC, which promoted the fusion of LDs and caused them to become larger. The enlarged LDs could not be degraded by autophagy, which ultimately led to accumulation of LDs. Conversely, FIS alleviated LD accumulation by inhibiting CIDEC-mediated fusion, resulting in smaller LDs that facilitated lipophagy. Additionally, studies indicated that the dysfunction of circadian rhythms is closely related to lipid metabolism. In our study, we showed that HFD and FFA disrupted circadian rhythm in C57BL/6 mouse hepatocytes and AML12 cells, while FIS modified the rhythm disturbances and increased protein expression of the core clocks BMAL1 and CLOCK. We silenced the BMAL1 protein and revealed that si-BMAL1 upregulated CIDEC proteins. These data suggested that FIS might inhibit CIDEC-mediated LD fusion and enhance hepatocyte lipophagy by promoting the expression of rhythm protein BMAL1, thereby alleviating LD accumulation in C57BL/6 and AML12 cells caused by the HFD and FFA. The present study provided novel insights and potential targets for utilizing functional food factors to mitigate the accumulation of LD in hepatocytes.
高脂饮食（HFD）会诱导肝细胞中脂滴（LDs）增大并积累，从而影响脂质代谢的稳态。细胞死亡诱导DNA片段化因子-α样效应因子C（CIDEC）是脂滴的一种表面蛋白，可促进其融合和生长，将小脂滴转化为大脂滴。脂质自噬是自噬的一种选择性形式，主要针对小脂滴进行降解。非瑟酮（FIS）是一种存在于各种水果和蔬菜中的天然膳食黄酮，其减少脂滴积累的机制尚不清楚。在本研究中，我们观察到FIS显著改善了HFD诱导的C57BL/6小鼠肝细胞中的脂质积累。在进一步的机制研究中，我们发现游离脂肪酸（FFA）增强了CIDEC的表达，促进了脂滴的融合并使其变大。增大的脂滴无法被自噬降解，最终导致脂滴积累。相反，FIS通过抑制CIDEC介导的融合来减轻脂滴积累，从而产生较小的脂滴，便于脂质自噬。此外，研究表明昼夜节律功能障碍与脂质代谢密切相关。在我们的研究中，我们发现HFD和FFA扰乱了C57BL/6小鼠肝细胞和AML12细胞中的昼夜节律，而FIS改善了节律紊乱并增加了核心生物钟蛋白BMAL1和CLOCK的表达。我们使BMAL1蛋白沉默，并发现si-BMAL1上调了CIDEC蛋白。这些数据表明，FIS可能通过促进节律蛋白BMAL1的表达来抑制CIDEC介导的脂滴融合并增强肝细胞脂质自噬，从而减轻HFD和FFA引起的C57BL/6和AML12细胞中的脂滴积累。本研究为利用功能性食品因子减轻肝细胞中脂滴积累提供了新的见解和潜在靶点。
