Abstract
Angiopoietin-like 8 (ANGPTL8) is a calorically responsive regulator of lipoprotein lipase (LPL). It does this by forming complexes with ANGPTL3 or ANGPTL4 that either inhibit LPL in oxidative tissues or preserve LPL activity in adipose tissue, respectively. Human heterozygous (reference allele/alternate allele, R/A) carriers of rs145464906/p.Q121X and rs760351239/p.Q131X ANGPTL8 protein truncating variants (PTVs) have favorable lipid profiles and decreased cardiovascular risk. Given the purported role of ANGPTL8 in redirecting circulating lipids in response to feeding, it is not clear why these PTVs should profile as they do. We elucidated this process by investigating these ANGPTL8 PTVs along with several novel ANGPTL8 putative loss of function (pLOF) variants, including a splice donor variant rs774984872/c.459 + 1G > T that was predicted to result in an ANGPTL8 truncation (p.K165X), in a consanguineous population from the Pakistan Genomic Resource (PGR). We observed lower TG, lower total cholesterol, and increased HDL-C in heterozygous carriers of these variants, consistent with previous reports for p.Q121X and p.Q131X and confirmed decreased ANGPTL3/8 and ANGPTL4/8 complex levels in serum samples from these carriers compared to non-carriers (R/R). Biochemically, the p.Q121X, p.Q131X and c.459 + 1G > T mutations showed dramatically reduced ANGPTL3/8 complex-mediated LPL inhibition while only modestly decreasing ANGPTL4/8-mediated preservation of LPL activity. Furthermore, a cohort of 14 participants that included 8 non-carriers, 5 heterozygous carriers and a single homozygous (A/A) individual of the c.459 + 1G > T pLOF variant were recruited for kinetic studies following standard mixed meal tolerance tests. Heterozygous carriers showed significantly reduced postprandial TG excursions compared to non-carriers. Together, these results support the concept that pLOF variants in ANGPTL8 result in favorable lipid profiles by selectively reducing ANGPTL3/8-mediated LPL inhibition while largely maintaining ANGPTL4/8-mediated preservation of LPL activity.
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Acknowledgements
We acknowledge Eli Lilly & Co. for providing funding to access the Pakistan Genomic Resource (PGR) database, conduct the ANGPTL8 pLoF recall-by-genotype study, and generate study biomarker data. Employees of Eli Lilly & Company contributed to the study design, analyses, decision to publish, and preparation of the manuscript. We express our gratitude to the participants of the PGR study for their cooperation in undergoing the standardized mixed-meal tolerance test (sMMTT). We appreciate the support from the CNCD staff in managing samples and thank Dr. Jonathan M. Wilson and Lenden Bowsman for samples handling at Eli Lilly & Co. Additionally, we extend our thanks to Mariam E. Ehani for her support making the recombinant proteins, as well as protein-stained gels and Western blots.
Funding
The recall-by-genotype (RBG) study was funded by Eli Lilly and Company. DS received project funding from Eli Lilly & Company, and ANGPTL8 targeted DNA sequencing was performed at the Center for Non-Communicable Diseases (CNCD).
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P.B, A.A, R.J.K, Y.Q.C, K.W, R.S, T.P.R, L.F.M, G.R, Y.W, E.Y.Z, M.H, T.P.B, D.D, Y.W.Q, H.L are full-time employees and stockholders at Eli Lilly and Company. No other potential competing interests relevant to this article were reported.
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Abadi, A., Chen, Y.Q., Khalid, S. et al. Unraveling the physiological impact of ANGPTL8 loss-of-function variants in humans. Sci Rep (2026). https://doi.org/10.1038/s41598-026-50362-z
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DOI: https://doi.org/10.1038/s41598-026-50362-z
