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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 6

A schematic showing the role of hepatic A8 and A3 in TG trafficking in the fed state.

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A schematic showing the role of hepatic A8 and A3 in TG trafficking in t...
(A) Expression of both A8 and A3 mRNA increase and A4 mRNA levels decrease with feeding (11). (1) A3 and A8 form a complex that inactivates intravascular LPL, which is most active in oxidative tissues. As a result, circulating TG is available for hydrolysis and uptake by adipose tissue. (2) Absence of A8 results in more TGs being available for uptake by oxidative tissues and less being available for uptake by adipose tissue. Glucose uptake, and its conversion to TG, are enhanced in adipose tissue of A8−/− mice. (3) TG trafficking in the Ls-A8−/− mice resembles that of the A8−/− mice (4) whereas TG trafficking in the As-A8−/− mice resembles that seen in the WT animals. (B) Levels of C16:1 (endogenously synthesized) and C18:2 and C18:3 (diet derived) in plasma and tissue lysates (adipose tissue and liver) were measured as described in the Methods, and the mean ratio (± SEM) of C16:1 to C18:2 plus C18:3 in each tissue is shown. Groups were compared using 1-way ANOVA with Dunnett’s multiple-comparisons test. *P < 0.05; ***P < 0.001; ****P < 0.0001.

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