Electronegative Low-Density Lipoprotein L5 Induces Adipose Tissue Inflammation Associated With Metabolic Syndrome

Abstract Context Electronegative low-density lipoprotein (LDL) L5 is a naturally occurring, atherogenic entity found at elevated levels in the plasma of patients with metabolic syndrome (MetS) in the absence of elevated plasma LDL levels. Objective To investigate the role of L5 in the mechanism of a...

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Published in:	The journal of clinical endocrinology and metabolism Vol. 102; no. 12; pp. 4615 - 4625
Main Authors:	Ke, Liang-Yin, Chan, Hua-Chen, Chan, Hsiu-Chuan, Kalu, Franklin Chikodi Udo, Lee, Hsiang-Chun, Lin, I-Ling, Jhuo, Shih-Jie, Lai, Wen-Ter, Tsao, Chen-Rong, Sawamura, Tatsuya, Dixon, Richard A, Chen, Chu-Huang, Chu, Chih-Sheng, Shin, Shyi-Jang
Format:	Journal Article
Language:	English
Published:	Washington, DC Endocrine Society 01-12-2017 Copyright Oxford University Press Oxford University Press
Subjects:	Adipocytes Adipocytes - metabolism Adipokines - metabolism Adipose tissue Adipose Tissue - metabolism Adipose Tissue - pathology Adult Aged Animals CD11c antigen CD11c Antigen - metabolism Cell culture Culture media Culture Media, Conditioned Electronegativity Etiology Humans Inflammation Inflammation - pathology Lipoproteins, LDL - pharmacology Liquid oxygen Low density lipoprotein LOX-1 protein Macrophages Male Mesocricetus Metabolic syndrome Metabolic Syndrome - metabolism Mice Mice, Inbred C57BL Mice, Knockout Middle Aged Monocytes Monocytes - metabolism Monocytes - pathology Scavenger Receptors, Class E - deficiency Scavenger Receptors, Class E - genetics Signal Transduction - genetics
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Summary:	Abstract Context Electronegative low-density lipoprotein (LDL) L5 is a naturally occurring, atherogenic entity found at elevated levels in the plasma of patients with metabolic syndrome (MetS) in the absence of elevated plasma LDL levels. Objective To investigate the role of L5 in the mechanism of adipose tissue inflammation associated with MetS. Patients/Setting Plasma LDL isolated from patients with MetS (n = 29) and controls (n = 29) with similar plasma LDL levels was separated into five subfractions, L1 to L5, with increasing electronegativity. Design We examined the invivo effects of L5 on adipose tissue in mice and the in vitro effects of L5 on adipocytokine signaling and monocytes. Results Tail-vein injection of human L5 but not L1 into C57BL/6 mice induced the accumulation of F4/80+ and CD11c+ M1 macrophages. The effects of L5 were attenuated in mice deficient for L5’s receptor, lectin-like oxidized LDL receptor 1 (LOX-1). L5 but not L1 induced human adipocytes to release inflammatory adipocytokines. Incubating human THP-1 monocytes with LDL-free culture media from L5-treated adipocytes enhanced the migration of monocytes by 300-fold (P < 0.001 vs L1-treated adipocyte media)—effects that were attenuated by LOX-1 neutralizing antibody. Migrated cells were positive for mature macrophage marker PM-2K, indicating the transformation of monocytes into macrophages. The infiltration of M1 macrophages in adipose tissue was also observed in a previously established hamster model of endogenously elevated L5. Conclusions L5 induces adipose inflammation through LOX-1 by promoting macrophage maturation and infiltration into adipose tissue. Elevated plasma L5 levels may be a novel etiology of adipose tissue inflammation in patients with MetS. We show in vivo and in vitro evidence supporting that L5 initiates obesity-associated inflammation by modulating the release of adipocytokines that attract and activate macrophages in adipose tissue.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0021-972X 1945-7197
DOI:	10.1210/jc.2017-01657