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<p>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 <i>Apoe</i><sup>−/−</sup> 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.</p>

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Cathelicidin LL-37-ApoB-100 interaction promotes LDL clearance and attenuates cholesterol accumulation in the liver

  • 期刊论文

  • 发表日期：

    2025年9月17日

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  • Yaqun Fang,
  • Zhiye Zhang,
  • Qiqi Cao,
  • Gan Wang,
  • Zilei Duan,
  • Ping Meng,
  • Shengwen Zhou,
  • Shuohan Fei,
  • Dawit Adisu Tadese,
  • James Mwangi,
  • Qiumin Lu,
  • Heyu Ni,
  • Ren Lai

摘要

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.