Fang Yaqun, Zhang Zhiye, Cao Qiqi, Wang Gan, Duan Zilei, Meng Ping, Zhou Shengwen, Fei Shuohan, Tadese Dawit Adisu, Mwangi James, Lu Qiumin, Ni Heyu, Lai Ren
Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Key Laboratory of Genetic Evolution & Animal Models, Sino-African Joint Research Center, and New Cornerstone Science Institute, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China.
Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650031, China.
Sci China Life Sci. 2025 Sep 17. doi: 10.1007/s11427-025-3006-2.
Dysregulation of low-density lipoprotein (LDL) cholesterol is strongly correlated with the risk of metabolic dysfunction-associated steatotic liver disease. Endogenous molecules targeting LDL clearance play crucial roles in the progression of liver steatosis. Human cathelicidin LL-37 can form complexes with lipoproteins, but whether these complexes regulate lipoprotein-driven cholesterol metabolism is not clear. Here, we find that cathelicidin LL-37 binds to LDL via apolipoprotein (Apo)B-100 domains, enhancing the solubility of ApoB-100 and inhibiting the modifications and aggregation of LDL. LL-37-LDL interaction promotes LDL uptake through LDL receptor (LDLR) both in hepatocytes and macrophages. This interaction also promotes LDL cholesterol clearance by facilitating cholesterol excretion and cholesterol efflux. In Apoe mice with hypercholesterolemia, the murine homolog cathelicidin Cramp similarly accelerates cholesterol clearance by activating cholesterol excretion and preventing hepatic lipid accumulation. This study identifies LL-37 as an endogenous regulator of LDL that promotes LDL cholesterol clearance.
低密度脂蛋白（LDL）胆固醇的调节异常与代谢功能障碍相关脂肪性肝病的风险密切相关。靶向LDL清除的内源性分子在肝脂肪变性的进展中起关键作用。人抗菌肽LL-37可与脂蛋白形成复合物，但这些复合物是否调节脂蛋白驱动的胆固醇代谢尚不清楚。在这里，我们发现抗菌肽LL-37通过载脂蛋白（Apo）B-100结构域与LDL结合，增强ApoB-100的溶解度并抑制LDL的修饰和聚集。LL-37-LDL相互作用促进肝细胞和巨噬细胞中通过LDL受体（LDLR）摄取LDL。这种相互作用还通过促进胆固醇排泄和胆固醇流出促进LDL胆固醇清除。在患有高胆固醇血症的Apoe小鼠中，鼠源同系物抗菌肽Cramp同样通过激活胆固醇排泄和防止肝脏脂质积累来加速胆固醇清除。这项研究确定LL-37是一种促进LDL胆固醇清除的LDL内源性调节剂。
