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. 2025 Jan 21;151(3):218-234.
doi: 10.1161/CIRCULATIONAHA.124.069272. Epub 2024 Oct 11.

Associations of Circulating ANGPTL3, C-Terminal Domain-Containing ANGPTL4, and ANGPTL3/8 and ANGPTL4/8 Complexes with LPL Activity, Diabetes, Inflammation, and Cardiovascular Mortality

Günther Silbernagel  1 , Yan Q Chen  2 , Hongxia Li  2 , Deven Lemen  2 , Yi Wen  2 , Eugene Y Zhen  2 , Martin Rief  3 , Marcus E Kleber  4   5 , Graciela E Delgado  4 , Mark A Sarzynski  6 , Yue-Wei Qian  2 , Boerge Schmidt  7 , Raimund Erbel  7 , Ulrike S Trampisch  8 , Angela P Moissl  9 , Henrik Rudolf  10 , Heribert Schunkert  11 , Andreas Stang  7   12 , Winfried März  13   4   14 , Hans J Trampisch  8 , Hubert Scharnagl  13 , Robert J Konrad  2
Affiliations

Associations of Circulating ANGPTL3, C-Terminal Domain-Containing ANGPTL4, and ANGPTL3/8 and ANGPTL4/8 Complexes with LPL Activity, Diabetes, Inflammation, and Cardiovascular Mortality

Günther Silbernagel et al. Circulation. .

Abstract

Background: ANGPTL3/4/8 (angiopoietin-like proteins 3, 4, and 8) are important regulators of LPL (lipoprotein lipase). ANGPTL8 forms complexes with ANGPTL3 and ANGPTL4. ANGPTL4/8 complex formation converts ANGPTL4 from a furin substrate to a plasmin substrate, and both cleavages generate similar C-terminal domain-containing (CD)-ANGPTL4 fragments. Whereas several studies have investigated associations of free ANGPTL proteins with cardiovascular risk, there are no data describing associations of the complexes and CD-ANGPTL4 with outcomes or describing the effects of the complexes on LPL bound to GPIHBP1 (glycosylphosphatidylinositol HDL-binding protein 1).

Methods: Recombinant protein assays were used to study ANGPTL protein and complex effects on GPIHBP1-LPL activity. ANGPTL3/8, ANGPTL3, ANGPTL4/8, and CD-ANGPTL4 were measured with dedicated immunoassays in 2394 LURIC (Ludwigshafen Risk and Cardiovascular Health) study participants undergoing coronary angiography and 6188 getABI study (German Epidemiological Trial on Ankle Brachial Index) participants undergoing ankle brachial index measurement. There was a follow-up for cardiovascular death with a median (interquartile range) duration of 9.80 (8.75-10.40) years in the LURIC study and 7.06 (7.00-7.14) years in the getABI study.

Results: ANGPTL3/8 potently inhibited GPIHBP1-LPL activity and showed positive associations with LDL-C (low-density lipoprotein cholesterol) and triglycerides (both P<0.001). However, in neither study did ANGPTL3/8 correlate with cardiovascular death. Free ANGPTL3 was positively associated with cardiovascular death in the getABI study but not the LURIC study. ANGPTL4/8 and especially CD-ANGPTL4 were positively associated with the prevalence of diabetes, CRP (C-reactive protein; all P<0.001), and cardiovascular death in both studies. In the LURIC and getABI studies, respective hazard ratios for cardiovascular mortality comparing the third with the first ANGPTL4/8 tertile were 1.47 (1.15-1.88) and 1.68 (1.25-2.27) when adjusted for sex, age, body mass index, and diabetes. For CD-ANGPTL4, these hazard ratios were 2.44 (1.86-3.20) and 2.76 (2.00-3.82).

Conclusions: ANGPTL3/8 potently inhibited GPIHBP1-LPL enzymatic activity, consistent with its positive association with serum lipids. However, ANGPTL3/8, LDL-C, and triglyceride levels were not associated with cardiovascular death in the LURIC and getABI cohorts. In contrast, concentrations of ANGPTL4/8 and particularly CD-ANGPTL4 were positively associated with inflammation, the prevalence of diabetes, and cardiovascular mortality.

Keywords: angiopoietin-like proteins; cardiovascular mortality; diabetes; inflammation; lipoprotein lipase.

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Conflict of interest statement

Y.Q.C., H.L., D.L., Y.W., E.Y.Z., Y-W.Q., and R.J.K. are Eli Lilly and Company employees and own Lilly stock. G.S. has received research funding from Numares AG, Sanofi, Bayer, and Eli Lilly, consulting fees from Sanofi, honoraria from Sanofi and Daiichi-Sankyo, meeting travel expenses from Bayer, Amgen, Daiichi-Sankyo, and research materials from Eli Lilly. H. Scharnagl has received research grants and support from Abbott Diagnostics and Amgen and honoraria from Amgen and Sanofi. M.E.K. has received employment from SYNLAB Holding, Deutschland. M.A.S. reports National Institutes of Health funding (R01NR019628, R01HL146462, R01DK128057) and has received consulting fees from Genetic Direction. H. Schunkert reports advisory fees from Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, and Servier, lecture fees/honoraria from AstraZeneca, Bayer Vital, Novartis, Servier, Sanofi-Aventis, Synlab, Bristol-Myers Squibb, medizinweltenfortbildung, CTI, Sciarc, and Amarin, and scientific grants from AstraZeneca, St Jude, and Boston Scientific. W.M. has received grants from Siemens, AstraZeneca, Bayer Vital, Bestbion Dx, Boehringer Ingelheim, Immundiagnostik, Merck Chemicals, and Olink, grants and personal fees from Aegerion, Amgen, Sanofi, Amryt Pharma, BASF, Abbott Diagnostics, Numares AG, Berlin-Chemie, Akzea Therapeutics, and Novartis, personal fees from Vifor Pharma, and employment from SYNLAB Holding Deutschland. The other authors report no conflicts.

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