Novel Jatrophane Diterpenoids from Euphorbia esula Promotes Lipid Clearance by Transcriptional Regulation of PCSK9

PCSK9 has been recognized as an efficient target for
hyperlipidemia
and related cardiovascular/cerebrovascular diseases. However, PCSK9
inhibitors in the clinic are all biological products, and no small
molecules are available yet. In the current work, we discovered that
the crude extract of Euphorbia esula (E. esula) promoted LDL uptake in vitro and then obtained 8 new and 12 known jatrophane
diterpenoids by activity-guided isolation. After summarized their
structure–activity relationship of PCSK9 inhibition, we selected
compound 11 (C11) with potent activity and high abundance to investigate
its mechanism and in vivo efficacy. Mechanistically,
C11 bound with HNF1α to influence its nuclear distribution and
subsequently inhibit PCSK9 transcription, thereby enhancing LDLR and
promoting LDL uptake. Moreover, C11 demonstrated obvious lipid-lowering
activity in HFD mouse model. In conclusion, we first revealed the
novel application of E. esula in the
discovery of a lipid-lowering candidate and highlighted the potential
of C11 in the treatment of hyperlipidemia.