An anti-ANGPTL3/8 antibody decreases circulating triglycerides by binding to a LPL-inhibitory leucine zipper-like motif

Balasubramaniam, Deepa; Schroeder, Oliver C.; Russell, Anna M.; Fitchett, Jonathan R.; Austin, Aaron K.; Beyer, Thomas P.; Chen, Yanqun; Day, Jonathan W.; Ehsani, Mariam; Heng, Aik Roy; Zhen, Yuejun; Davies, Julian; Glaesner, Wolfgang; Jones, Bryan E.; Siegel, Robert W.; Qian, Yue‐Wei; Konrad, Robert J.

doi:10.1016/j.jlr.2022.100198

Cited by 29 publications

(52 citation statements)

References 95 publications

(162 reference statements)

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“…[134] Very recently, our group has shown that evinacumab indeed acts to block the ANGPTL3/8 complex in addition to inhibiting ANGPTL3. [146] We also demonstrated that an anti-ANGPTL3/8 complex-specific mAb, produced by immunizing humanized mice with recombinant ANGPTL3/8 complex, can selectively block the ability of ANGPTL3/8 to inhibit LPL, without affecting the ability of ANGPTL3 to inhibit LPL. [146] Consequently, a single dose of this anti-ANGPTL3/8 antibody was administered to hypertriglyceridemic mice and dramatically decreased their circulating TG levels (maximal TG reductions of 80-90%) for up to 28 d in a dose-dependent manner.…”

Section: Angptl3/8mentioning

confidence: 76%

“…[146] We also demonstrated that an anti-ANGPTL3/8 complex-specific mAb, produced by immunizing humanized mice with recombinant ANGPTL3/8 complex, can selectively block the ability of ANGPTL3/8 to inhibit LPL, without affecting the ability of ANGPTL3 to inhibit LPL. [146] Consequently, a single dose of this anti-ANGPTL3/8 antibody was administered to hypertriglyceridemic mice and dramatically decreased their circulating TG levels (maximal TG reductions of 80-90%) for up to 28 d in a dose-dependent manner. [146] Hydrogen-deuterium exchange mass-spectrometry (HDXMS) and molecular modeling revealed that this anti-ANGPTL3/8 antibody, LPL, and ApoA5 all bound to the same LPL-inhibitory epitope present in the ANGPTL3/8 complex.…”

Section: Angptl3/8mentioning

confidence: 76%

“…[141,144] Very recently, our laboratory demonstrated that ApoA5 competes with LPL for binding to a unique LPL-inhibitory epitope present in the ANGPTL3/8 complex and in so doing protects LPL from ANGPTL3/8-mediated LPL inhibition, thereby providing the likely mechanism through which ApoA5 acts to lower circulating TG levels. [145,146] In humans, LOF mutations and lower ApoA5 concentrations are associated with elevated TG levels and reduced HDL-C. [32,135,[147][148][149][150][151][152][153][154][155] In one study, the associations of the -1131T > C promoter polymorphism with lipids and coronary heart disease were assessed. [150] Per each C allele, the TG concentration increased by 22 mg dL -1 while HDL-C decreased by 2 mg dL -1 .…”

Section: Apoa5mentioning

confidence: 99%

“…[146] Consequently, a single dose of this anti-ANGPTL3/8 antibody was administered to hypertriglyceridemic mice and dramatically decreased their circulating TG levels (maximal TG reductions of 80-90%) for up to 28 d in a dose-dependent manner. [146] Hydrogen-deuterium exchange mass-spectrometry (HDXMS) and molecular modeling revealed that this anti-ANGPTL3/8 antibody, LPL, and ApoA5 all bound to the same LPL-inhibitory epitope present in the ANGPTL3/8 complex. [146] This unique epitope, which contains a leucine zipper-like motif, was comprised of the interacting N-terminal regions of ANGPTL3 and ANGPTL8 in the ANGPTL3/8 complex.…”

Section: Angptl3/8mentioning

confidence: 99%

“…[146] Hydrogen-deuterium exchange mass-spectrometry (HDXMS) and molecular modeling revealed that this anti-ANGPTL3/8 antibody, LPL, and ApoA5 all bound to the same LPL-inhibitory epitope present in the ANGPTL3/8 complex. [146] This unique epitope, which contains a leucine zipper-like motif, was comprised of the interacting N-terminal regions of ANGPTL3 and ANGPTL8 in the ANGPTL3/8 complex. [146] These data also shed light on the TG lowering mechanism of ApoA5 by suggesting that ApoA5 may compete with LPL for binding to the LPL-inhibitory epitope present in ANGPTL3/8, thereby protecting LPL from ANGPTL3/8-mediated inhibition.…”

Section: Angptl3/8mentioning

confidence: 99%

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The Regulation of Triacylglycerol Metabolism and Lipoprotein Lipase Activity

2022

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Triacylglycerol (TG) metabolism is tightly regulated to maintain a pool of TG within circulating lipoproteins that can be hydrolyzed in a tissue‐specific manner by lipoprotein lipase (LPL) to enable the delivery of fatty acids to adipose or oxidative tissues as needed. Elevated serum TG concentrations, which result from a deficiency of LPL activity or, more commonly, an imbalance in the regulation of tissue‐specific LPL activities, have been associated with an increased risk of atherosclerotic cardiovascular disease through multiple studies. Among the most critical LPL regulators are the angiopoietin‐like (ANGPTL) proteins ANGPTL3, ANGPTL4, and ANGPTL8, and a number of different apolipoproteins including apolipoprotein A5 (ApoA5), apolipoprotein C2 (ApoC2), and apolipoprotein C3 (ApoC3). These ANGPTLs and apolipoproteins work together to orchestrate LPL activity and therefore play pivotal roles in TG partitioning, hydrolysis, and utilization. This review summarizes the mechanisms of action, epidemiological findings, and genetic data most relevant to these ANGPTLs and apolipoproteins. The interplay between these important regulators of TG metabolism in both fasted and fed states is highlighted with a holistic view toward understanding key concepts and interactions. Strategies for developing safe and effective therapeutics to reduce circulating TG by selectively targeting these ANGPTLs and apolipoproteins are also discussed.

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Section: Angptl3/8mentioning

confidence: 76%

Section: Angptl3/8mentioning

confidence: 76%

Section: Apoa5mentioning

confidence: 99%

Section: Angptl3/8mentioning

confidence: 99%

Section: Angptl3/8mentioning

confidence: 99%

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The Regulation of Triacylglycerol Metabolism and Lipoprotein Lipase Activity

2022

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Plasma insulin is required for the increase in plasma angiopoietin‐like protein 8 in response to nutrient ingestion

Alatrach¹,

Abubaker

Al-Khairi

et al. 2023

Diabetes Metabolism Res

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BackgroundPlasma levels of angiopoietin‐like protein 8 (ANGPTL8) are regulated by feeding and they increase following glucose ingestion. Because both plasma glucose and insulin increase following food ingestion, we aimed to determine whether the increase in plasma insulin and glucose or both are responsible for the increase in ANGPTL8 levels.MethodsANGPTL8 levels were measured in 30 subjects, 14 with impaired fasting glucose (IFG), and 16 with normal fasting glucose (NFG); the subjects received 75g glucose oral Glucose tolerance test (OGTT), multistep euglycaemic hyperinsulinemic clamp and hyperglycaemic clamp with pancreatic clamp.ResultsSubjects with IFG had significantly higher ANGPTL8 than NGT subjects during the fasting state (p < 0.05). During the OGTT, plasma ANGPTL8 concentration increased by 62% above the fasting level (p < 0.0001), and the increase above fasting in ANGPTL8 levels was similar in NFG and IFG individuals. During the multistep insulin clamp, there was a dose‐dependent increase in plasma ANGPTL8 concentration. During the 2‐step hyperglycaemic clamp, the rise in plasma glucose concentration failed to cause any change in the plasma ANGPTL8 concentration from baseline.ConclusionsIn response to nutrient ingestion, ANGPTL8 level increased due to increased plasma insulin concentration, not to the rise in plasma glucose. The incremental increase above baseline in plasma ANGLPTL8 during OGTT was comparable between people with normal glucose tolerance and IFG.

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