Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids

Yan Q Chen,Thomas G Pottanat,Robert W Siegel,Mariam Ehsani,Yue-Wei Qian,Eugene Y Zhen,Ajit Regmi,William C Roell,Haihong Guo,M Jane Luo,Ruth E Gimeno,Ferdinand Van'T Hooft,Robert J Konrad

doi:10.1194/jlr.ra120000781

Yan Q Chen, Thomas G Pottanat + Show 11 more

Open Access

https://doi.org/10.1194/jlr.ra120000781

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Abstract

Angiopoietin-like protein (ANGPTL)8 has been implicated in metabolic syndrome and reported to regulate adipose FA uptake through unknown mechanisms. Here, we studied how complex formation of ANGPTL8 with ANGPTL3 or ANGPTL4 varies with feeding to regulate LPL. In human serum, ANGPTL3/8 and ANGPTL4/8 complexes both increased postprandially, correlated negatively with HDL, and correlated positively with all other metabolic syndrome markers. ANGPTL3/8 also correlated positively with LDL-C and blocked LPL-facilitated hepatocyte VLDL-C uptake. LPL-inhibitory activity of ANGPTL3/8 was >100-fold more potent than that of ANGPTL3, and LPL-inhibitory activity of ANGPTL4/8 was >100-fold less potent than that of ANGPTL4. Quantitative analyses of inhibitory activities and competition experiments among the complexes suggested a model in which localized ANGPTL4/8 blocks the LPL-inhibitory activity of both circulating ANGPTL3/8 and localized ANGPTL4, allowing lipid sequestration into fat rather than muscle during the fed state. Supporting this model, insulin increased ANGPTL3/8 secretion from hepatocytes and ANGPTL4/8 secretion from adipocytes. These results suggest that low ANGPTL8 levels during fasting enable ANGPTL4-mediated LPL inhibition in fat tissue to minimize adipose FA uptake. During feeding, increased ANGPTL8 increases ANGPTL3 inhibition of LPL in muscle via circulating ANGPTL3/8, while decreasing ANGPTL4 inhibition of LPL in adipose tissue through localized ANGPTL4/8, thereby increasing FA uptake into adipose tissue. Excessive caloric intake may shift this system toward the latter conditions, possibly predisposing to metabolic syndrome.

Highlights

Angiopoietin-like protein (ANGPTL)8 has been implicated in metabolic syndrome and reported to regulate adipose FA uptake through unknown mechanisms
At its most basic level, metabolic syndrome manifests as Abbreviations: ANGPTL, angiopoietin-like protein; Basal insulin peglispro (BIL), basal insulin peglispro; CTDC, C-terminal domain-containing; glucose-dependent insulinotropic peptide (GIP), glucosedependent insulinotropic peptide; HSA, human serum albumin; MRM, multiple reaction monitoring; MSD, Meso Scale Discovery; Ni-NTA, nickel-nitrilotriacetic acid; PECF, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-carboxyfluorescein; PL, phospholipid; SEC, size exclusion chromatography; SIL, stable-isotope-labeled
We show that ANGPTL4/8 can prevent ANGPTL3/8 from inhibiting LPL, thereby providing a mechanism to allow for LPL in the adipose tissue to be protected from increased postprandial circulating ANGPTL3/8 levels

Summary

Introduction

Angiopoietin-like protein (ANGPTL)8 has been implicated in metabolic syndrome and reported to regulate adipose FA uptake through unknown mechanisms. Our data demonstrate how increased ANGPTL8 levels that occur following feeding can decrease LPL activity in the skeletal muscle while increasing LPL activity in the fat, directing postprandial uptake of FA into adipose tissue. We utilized a mass spectrometry LC-MRM method with SIL peptides to ascertain the molar ratios of the respective proteins in the recombinant ANGPTL3/8 and ANGPTL4/8 complexes.

Results

Conclusion