ANGPTL8 has both endocrine and autocrine effects on substrate utilization
Federico Oldoni, Haili Cheng, Serena Banfi, Viktoria Gusarova, Jonathan C. Cohen, Helen H. Hobbs
Federico Oldoni, Haili Cheng, Serena Banfi, Viktoria Gusarova, Jonathan C. Cohen, Helen H. Hobbs
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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 4

A8 protein and mRNA levels in WAT and BAT of mice of the indicated genotypes.

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A8 protein and mRNA levels in WAT and BAT of mice of the indicated genot...
(A) Immunoblot analysis of A8 in tissue lysates from WAT-SQ and BAT (25 μg each) of chow-fed male mice (n = 3–4/genotype, 12–13 weeks) was performed as described in the Methods. All experiments were performed in refed conditions. Pooled data from 2 experiments (n = 3–4/group for each experiment) are shown. Band intensities were normalized to the level of calnexin and then expressed relative to WT. (B) mRNA levels of A8 and A4 were determined by real-time PCR in chow-fed male mice (n = 6/group, 12–13 weeks). Values are expressed as ratios compared with the mean level in WT littermates, which was set at 1. Ct values in the WT mice are provided. ***P < 0.001; ****P < 0.0001. Groups were compared using 2-way ANOVA. The experiments were repeated twice and the results were similar.