TY - JOUR
T1 - ANGPTL8 has both endocrine and autocrine effects on substrate utilization
AU - Oldoni, Federico
AU - Cheng, Haili
AU - Banfi, Serena
AU - Gusarova, Viktoria
AU - Cohen, Jonathan C.
AU - Hobbs, Helen H.
N1 - Funding Information:
We thank Christina Zhao, Liangcai Nie, Fang Xu, Tommy Hyatt, Maritza Thomas, and Lisa Beatty for technical support; Julia Kozlitina for statistical advice; and Fabienne Elwood for administrative support. JCC and HHH were supported by grants from the NIH (5 PO1 HL20948).
Publisher Copyright:
© 2020, Oldoni et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2020/9/3
Y1 - 2020/9/3
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.138777
DO - 10.1172/jci.insight.138777
M3 - Article
C2 - 32730227
AN - SCOPUS:85090267459
SN - 2379-3708
VL - 5
JO - JCI Insight
JF - JCI Insight
IS - 17
M1 - e138777
ER -