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ANGPTL8 has both endocrine and autocrine effects on substrate utilization
Federico Oldoni, … , Jonathan C. Cohen, Helen H. Hobbs
Federico Oldoni, … , Jonathan C. Cohen, Helen H. Hobbs
Published July 30, 2020
Citation Information: JCI Insight. 2020;5(17):e138777. https://doi.org/10.1172/jci.insight.138777.
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Research Article Endocrinology Metabolism

ANGPTL8 has both endocrine and autocrine effects on substrate utilization

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Abstract

The angiopoietin-like protein ANGPTL8 (A8) is one of 3 ANGPTLs (A8, A3, A4) that coordinate changes in triglyceride (TG) delivery to tissues by inhibiting lipoprotein lipase (LPL), an enzyme that hydrolyzes TG. Previously we showed that A8, which is expressed in liver and adipose tissue, is required to redirect dietary TG from oxidative to storage tissues following food intake. Here we show that A8 from liver and adipose tissue have different roles in this process. Mice lacking hepatic A8 have no circulating A8, high intravascular LPL activity, low plasma TG levels, and evidence of decreased delivery of dietary lipids to adipose tissue. In contrast, mice lacking A8 in adipose tissue have higher postprandial TG levels and similar intravascular LPL activity and plasma A8 levels and higher levels of plasma TG. Expression of A8, together with A4, in cultured cells reduced A4 secretion and A4-mediated LPL inhibition. Thus, hepatic A8 (with A3) acts in an endocrine fashion to inhibit intravascular LPL in oxidative tissues, whereas A8 in adipose tissue enhances LPL activity by autocrine/paracrine inhibition of A4. These combined actions of A8 ensure that TG stores are rapidly replenished and sufficient energy is available until the next meal.

Authors

Federico Oldoni, Haili Cheng, Serena Banfi, Viktoria Gusarova, Jonathan C. Cohen, Helen H. Hobbs

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Figure 8

A8 inhibits A4-mediated LPL degradation by interacting with A4.

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A8 inhibits A4-mediated LPL degradation by interacting with A4.
(A) A8 p...
(A) A8 physically interacts with A4 in QBI-293 cells. Recombinant A4-Myc and A8-Flag were coexpressed in QBI-293 cells alone (with empty plasmid) or together. A4 was immunoprecipitated using Myc-linked magnetic beads (left panel), and A8 was immunoprecipitated using Flag magnetic beads (right panel) as described in the Methods. As A4 has nonspecific binding to magnetic beads, Flag beads were eluted using 3× Flag peptide. Immunoblot analysis using anti-A4 (top), anti-A8 (middle), and anti-calnexin antibodies was performed using 30 μg of lysate (input) as described in Methods. (B) Schematic model of A4, A8, and LPL expression in WAT from fasted (top) and refed (bottom) mice. After a 15-hour fast, no A8 is present in the adipose tissue of WT mice whereas levels of expression of A4 are high. A4 expression promotes degradation of LPL. As a consequence, circulating lipoproteins bypass WAT and deliver TGs to oxidative tissues (top). In the fasting to feeding transition, A8 expression rises as levels of A4 slowly fall. A8 interacts with A4, thus sparing LPL from A4-stimulated intracellular degradation. LPL is now available to hydrolyze circulating lipoprotein-TGs and thus replete TG stores in adipose tissue when food is available.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

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