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

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 7

A8 prevents A4 secretion and attenuates A4 inhibition of LPL in CHO-K1 cells and in 3T3-L1 adipocytes.

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A8 prevents A4 secretion and attenuates A4 inhibition of LPL in CHO-K1 c...
(A) Equimolar amounts of control (empty plasmid) and recombinant A4 and A8 were expressed in CHO-K1 cells alone or together. Whole-cell lysates, the heparin-released fraction, and conditioned medium were subjected to SDS-PAGE and immunoblotting using anti-A4 (top), anti-A8 (middle), and anti-calnexin antibodies as described in the Methods. (B) CHO-K1 cells were cotransfected with control, A4, A8, and LPL plasmids as indicated. The LPL activity was assayed in the medium 48 hours after transfection, as described in the Methods. (C) Differentiated 3T3-L1 adipocytes were infected with control and single or combination of A8 and A4 adenoviruses as described in the Methods. After 24 hours, cells and medium were collected, and immunoblot analysis was performed using anti-A4 (top), anti-A8 (middle), and anti-calnexin antibodies on cell lysates and cultured medium. The experiments were performed 2 additional times and the results were similar.