ESPE Yearbook of Paediatric Endocrinology

Cell Metabolism 2022;34(5):667-80.e6. doi: 10.1016/j.cmet.2022.03.006

Brief Summary: In preclinical models and a phase 1 trial, a powerful new lipid small molecule was shown to act through a mechanism distinct from those of known hypolipidemic agents. Targeting HNF-1α may be a new therapeutic strategy.

Comment: Familial hypercholesterolemia (FH) is the most common autosomal-dominant genetic disorder. Loss-of-function mutations in the low-density lipoprotein receptor (LDLR) and apolipoprotein B, as well as gain-of-function mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9), account for the vast majority of FH cases.

HMG-CoA reductase inhibitors, or statins, are the recommended first-line therapy for most FH patients. However, statin monotherapy is often insufficient to lower LDL cholesterol (LDL-C) to target levels. The addition of a PCSK9 inhibitor (alirocumab and evolocumab) further reduces LDL-C by 43% to 64%. Angiopoietin-like 3 (ANGPTL3) is an endogenous inhibitor of lipoprotein lipase (LPL) and endothelial lipase. A human monoclonal antibody to target and inhibit ANGPTL3 (evinacumab, approved by the FDA in February 2021) reduces LDL-C by up to 23%, and fasting TG levels by up to 76%. This reduction in lipid levels is independent of the LDLR, thus providing hope to individuals with homozygous FH.

This study used an extract from Corydalis ambigua, a herb used for centuries in traditional Chinese medicine. They identified a molecule that had a potent lipid-lowering effect both in vitro and in animal models. Given its good pharmacological profile and low toxicity, it was selected for a clinical trial. After one month of treatment, serum levels of LDL-C and TG decreased by 19% and 27%, respectively. The molecule downregulated PCSK9 and ANGPTL3 transcription by interfering with the binding of HNF-1α to its HNF-1 response element on these two gene promoters. Secondary to PCSK9 down-regulation, LDLR expression was upregulated. Lower ANGPTL3 expression enhanced lipoprotein lipase activity. Finally, the combination of the new molecule with atorvastatin had an additive effect on lipid clearance, overcoming the elevated PCSK9 levels caused by statin treatment.

Reference: 1. Akyea RK, Kai J, Qureshi N, Iyen B, Weng SF. Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease. 2019;105(13):975-81. doi: 10.1136/heartjnl-2018-314253.