Li Lu, Lin Jieru, Huang Chunhuan, Liu Jiamiao, Yuan Yi, Liu Zhenxing, Li Yuyin, Li Wei, Diao Aipo
School of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China.
School of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China.
Biochem Pharmacol. 2025 Feb;232:116694. doi: 10.1016/j.bcp.2024.116694. Epub 2024 Dec 4.
The balance between lipid synthesis and lipid catabolism is critical to maintain energy homeostasis. Lipophagy and lipolysis are two important pathways for lipid selective catabolism. Defects in lipophagy and lipolysis are linked to lipid metabolic diseases. Transcription factor EB (TFEB) is a master regulator of autophagy and lysosome biogenesis, as well as lipid metabolism by promoting expression of genes encoding fat catabolic lipases. Therefore, targeting TFEB provides a novel potential strategy for the treatment of lipid metabolic diseases. In this study, we showed that the TFEB activator clomiphene citrate (CC) activated the autophagy-lysosome and lipolysis pathways, and promoted degradation of lipid droplets induced by the free fatty acids oleate and palmitate in HepG2 cells. Moreover, CC treatment promoted lipid catabolism and attenuated obesity, restored lipid levels, blood glucose levels and insulin resistance, hepatocellular injury and hepatic steatosis, as well as liver inflammation in the HFD fed mice. In addition, we found that En-CC, a trans-isomer of CC, displayed less toxicity and more efficient activation of TFEB. Consistent with CC, En-CC treatment improved lipid metabolic syndrome pathology. These findings demonstrate that CC promotes clearance of lipids and ameliorates HFD-induced lipid metabolic syndrome pathology through activating TFEB-mediated lipophagy and lipolysis, indicating that CC has the potential to be used to treat lipid metabolic diseases.
脂质合成与脂质分解之间的平衡对于维持能量稳态至关重要。脂质自噬和脂解是脂质选择性分解代谢的两个重要途径。脂质自噬和脂解缺陷与脂质代谢疾病相关。转录因子EB（TFEB）是自噬和溶酶体生物发生以及脂质代谢的主要调节因子，它通过促进编码脂肪分解脂肪酶的基因表达来调节脂质代谢。因此，靶向TFEB为治疗脂质代谢疾病提供了一种新的潜在策略。在本研究中，我们发现TFEB激活剂枸橼酸氯米芬（CC）激活了自噬-溶酶体和脂解途径，并促进了油酸和棕榈酸等游离脂肪酸诱导的HepG2细胞中脂滴的降解。此外，CC处理促进了脂质分解代谢，减轻了肥胖，恢复了高脂饮食喂养小鼠的脂质水平、血糖水平和胰岛素抵抗、肝细胞损伤和肝脂肪变性以及肝脏炎症。此外，我们发现CC的反式异构体En-CC毒性较小，对TFEB的激活效率更高。与CC一致，En-CC处理改善了脂质代谢综合征的病理状态。这些发现表明，CC通过激活TFEB介导的脂质自噬和脂解促进脂质清除并改善高脂饮食诱导的脂质代谢综合征病理状态，表明CC有潜力用于治疗脂质代谢疾病。
