Liang-Yin Ke1,2,3,4, Hua-Chen Chan1,3,4, Hsiu-Chuan Chan3, Franklin Chikodi Udo Kalu2, Hsiang-Chun Lee3,5, I-Ling Lin2, Shih-Jie Jhuo5, Wen-Ter Lai3,5, Chen-Rong Tsao6, Tatsuya Sawamura7, Richard A Dixon8, Chu-Huang Chen1,3,4,9,10, Chih-Sheng Chu3,4,5, Shyi-Jang Shin3,10,11. 1. Vascular and Medicinal Research, Texas Heart Institute. 2. Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Taiwan. 3. Lipid Science and Aging Research Center, Kaohsiung Medical University, Taiwan. 4. Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Taiwan. 5. Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Taiwan. 6. Division of Cardiology, Department of Internal Medicine, Feng Yuan Hospital, Ministry of Health, Taiwan. 7. Department of Physiology, School of Medicine, Shinshu University, Japan. 8. Department of Molecular Cardiology, Texas Heart Institute. 9. New York Heart Research Foundation. 10. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Taiwan. 11. Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Medical University Hospital, Taiwan.
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.
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 humanTHP-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.
Authors: Der-Yuan Chen; Tatsuya Sawamura; Richard A F Dixon; José Luis Sánchez-Quesada; Chu-Huang Chen Journal: J Clin Med Date: 2021-05-06 Impact factor: 4.241