Genetic Mimicry Analysis Reveals the Specific Lipases Targeted by the ANGPTL3-ANGPTL8 Complex and ANGPTL4

Angiopoietin-like proteins, ANGPTL3, ANGPTL4, and ANGPTL8, are involved in regulating plasma lipids. In vitro and animal-based studies point to LPL and endothelial lipase (EL, LIPG) as key targets of ANGPTLs. To examine the ANGPTL mechanisms for plasma lipid modulation in humans, we pursued a genetic mimicry analysis of enhancing or suppressing variants in the LPL, LIPG, lipase C hepatic type (LIPC), ANGPTL3, ANGPTL4, and ANGPTL8 genes using data on 248 metabolic parameters derived from over 110,000 nonfasted individuals in the UK Biobank and vali-dated in over 13,000 overnight fasted individuals from 11 other European populations. ANGPTL4 sup-pression was highly concordant with LPL enhance-ment but not HL or EL, suggesting ANGPTL4 impacts plasma metabolic parameters exclusively via LPL. The LPL-independent effects of ANGPTL3 suppression on plasma metabolic parameters showed a striking inverse resemblance with EL suppression, suggesting ANGPTL3 not only targets LPL but also targets EL. Investigation of the impact of the ANGPTL3-ANGPTL8 complex on plasma metabolite traits via the ANGPTL8 R59W substitution as an instrumental variable showed a much higher concor-dance between R59W and EL activity than between R59W and LPL activity, suggesting the R59W sub-stitution more strongly affects EL inhibition than LPL inhibition. Meanwhile, when using a rare and deleterious protein-truncating ANGPTL8 variant as an instrumental variable, the ANGPTL3-ANGPTL8 complex was very LPL specific. In conclusion, our analysis provides strong human genetic evidence that the ANGPTL3-ANGPTL8 complex regulates plasma metabolic parameters, which is achieved by impacting LPL and EL. By contrast, ANGPTL4 influences plasma metabolic parameters exclusively via LPL.

Automated summary

Angiopoietin-like proteins (ANGPTL3, ANGPTL4, and ANGPTL8) play a role in regulating plasma lipids. This study analyzed genetic variants in several genes related to lipid metabolism and found that ANGPTL4 primarily affects plasma metabolic parameters through LPL. On the other hand, ANGPTL3 affects these parameters by targeting both LPL and EL. The impact of the ANGPTL3-ANGPTL8 complex was found to be stronger on EL inhibition than on LPL inhibition. Overall, this analysis provides strong genetic evidence for the involvement of the ANGPTL3-ANGPTL8 complex in regulating plasma metabolic parameters.