Decoding the role of angiopoietin-like protein 4/8 complex-mediated plasmin generation in the regulation of LPL activity

Yan Q Chen; Eugene Y Zhen; Anna M Russell; Mariam Ehsani; Robert W Siegel; Yuewei Qian; Robert J Konrad

doi:10.1016/j.jlr.2023.100441

Decoding the role of angiopoietin-like protein 4/8 complex-mediated plasmin generation in the regulation of LPL activity

J Lipid Res. 2023 Oct;64(10):100441. doi: 10.1016/j.jlr.2023.100441. Epub 2023 Sep 4.

Authors

Yan Q Chen¹, Eugene Y Zhen¹, Anna M Russell¹, Mariam Ehsani¹, Robert W Siegel¹, Yuewei Qian¹, Robert J Konrad²

Affiliations

¹ Lilly Research Laboratories, Eli Lilly, and Company, Indianapolis, IN, USA.
² Lilly Research Laboratories, Eli Lilly, and Company, Indianapolis, IN, USA. Electronic address: konrad_robert@lilly.com.

Abstract

After feeding, adipose tissue lipoprotein lipase (LPL) activity should be maximized, therefore the potent LPL-inhibitory activity of angiopoietin-like protein 4 (ANGPTL4) must be blocked by ANGPTL8 through formation of ANGPTL4/8 complexes. ANGPTL4/8 tightly binds and protects LPL but also partially inhibits its activity. Recently, we demonstrated ANGPTL4/8 also binds tissue plasminogen activator (tPA) and plasminogen to generate plasmin that cleaves ANGPTL4/8 to restore LPL activity. Although fully active LPL in the fat postprandially is desirable, ANGPTL4/8 removal could subject LPL to profound inhibition by ANGPTL3/8 (the most potent circulating LPL inhibitor), inhibition by other LPL inhibitors like ANGPTL4, ANGPTL3, and ApoC3 or interfere with ApoC2-mediated LPL activation. To understand better these potential paradoxes, we examined LPL inhibition by ANGPTL3/8, ANGPTL4, ANGPTL3, and ApoC3 and LPL stimulation by ApoC2 in the presence of ANGPTL4/8 + tPA + plasminogen. Remarkably, ANGPTL3/8-mediated LPL inhibition was almost completely blocked, with the mechanism being cleavage of fibrinogen-like domain-containing ANGPTL3 present in the ANGPTL3/8 complex. The LPL-inhibitory effects of ANGPTL4, ANGPTL3, and ApoC3 were also largely reduced in the presence of ANGPTL4/8 + tPA + plasminogen. In contrast, the ability of ApoC2 to stimulate LPL activity was unaffected by ANGPTL4/8-mediated plasmin generation. Together, these results explain how plasmin generated by increased postprandial ANGPTL4/8 levels in adipose tissue enables maximal LPL activity by preventing ANGPTL3/8, ANGPTL4, ANGPTL3, and ApoC3 from inhibiting LPL, while permitting ApoC2-mediated LPL activation to occur.

Keywords: angiopoietin-like protein (ANGPTL); apolipoprotein (Apo); lipoprotein lipase (LPL); plasmin; plasminogen; tissue plasminogen activator (tPA); triglycerides (TG).