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<p>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 <i>ANGPTL8</i> 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 <i>ANGPTL8</i> PTVs along with several novel <i>ANGPTL8</i> putative loss of function (pLOF) variants, including a splice donor variant rs774984872/c.459 + 1G &gt; 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 &gt; 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 &gt; 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 <i>ANGPTL8</i> result in favorable lipid profiles by selectively reducing ANGPTL3/8-mediated LPL inhibition while largely maintaining ANGPTL4/8-mediated preservation of LPL activity.</p>

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Unraveling the physiological impact of ANGPTL8 loss-of-function variants in humans

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月29日

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  • Arkan Abadi,
  • Yan Q. Chen,
  • Shareef Khalid,
  • Kylia Williams,
  • Eugene Y. Zhen,
  • Hongxia Li,
  • Robert Siegel,
  • Maryalice Hartley,
  • Thomas Patrick Beyer,
  • Danisha DeBowles,
  • Yue-Wei Qian,
  • Asif Rahseed,
  • Maleeha Zaman Khan,
  • Muhammad Jahanzaib,
  • Muhammad Rehan Mian,
  • Riffat Sultana,
  • Anjum Jalal,
  • Shahid Abbas,
  • Ambreen Muddassir,
  • Saima Naz Mohsin,
  • Shahid Mukhtar,
  • Adil Mahmood,
  • Timothy P. Ryan,
  • Laura F. Michael,
  • Giacomo Ruotolo,
  • Danish Saleheen,
  • Yi Wen,
  • Robert J. Konrad,
  • Pallav Bhatnagar

摘要

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.