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 1

Body weights and rectal temperatures of tissue-specific A8 knockout mice.

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Body weights and rectal temperatures of tissue-specific A8 knockout mice...
(A) Schematic of mouse A8, the targeting vector, the targeted allele, the targeted ΔNeo allele, and the disrupted A8 allele. LoxP sites were placed upstream of exons 1 and in intron 2. A rox-Dre-NEO-rox-loxP cassette was inserted in intron 2. After selection for neomycin (Neo), Dre recombinase was expressed to excise the Neo cassette. Mice with the targeted ΔNeo allele (fl/fl) were crossed with mice expressing Cre under the control of the albumin or adiponectin promoter to inactivate A8 in hepatocytes (Ls-A8–/– mice) or in adipocytes (As-A8–/– mice). (B) Mean (± SEM) body weights were determined, and then fat mass and lean body mass of chow-fed male mice (n = 13–28/genotype, 9–10 weeks) were measured using nuclear magnetic resonance (NMR). (C) Male mice (n = 6–9/genotype, 9–10 weeks) were maintained at room temperature (21°C–23°C). Rectal temperatures were obtained at the end of a 15-hour fast (left) and then 4 hours after chow was provided to the mice (right). The experiments were repeated 3 times and the results were similar. Values are shown as means ± SEM. Groups were compared using 1-way ANOVA with Dunnett’s multiple-comparisons test. **P < 0.01; ***P < 0.001.