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The gastrointestinal tract is involved in physiological regulation, including regulation of metabolism and feeding behavior, through the secretion of gut hormones and generation of signals via receptors in response to nutrients. Several G protein-coupled receptors (GPCRs) have been identified as sensors of lipids, such as fatty acids, monoacylglycerols (MAGs), and their metabolites, the levels of which are increased in the intestine after meals. GPR40 and 120 are well-known receptors for dietary long-chain fatty acids and their metabolites produced by gut microbiota. In addition, GPR119 is a receptor for MAGs [i.e. 2-oleoylglycerol (2-OG)], lysophosphatidylcholine (LPC), and fatty acid ethanolamides (FAEs) [i.e. oleoylethanolamide (OEA)]. Although enterocytes, enteroendocrine cells, and neural fibers have been postulated to sense lipids via GPCRs in the gut, most studies imply that enteroendocrine cells are the primary cells that sense lipids, which results in the production of hormones like cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) after a meal.

Miki Igarashi, Tetsuhiko Hayakawa, Haruka Tanabe, Keita Watanabe, ... Ikuo Kimura

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Scavenging dicarbonyls with 5′-O-pentyl-pyridoxamine increases HDL net cholesterol efflux capacity and attenuates atherosclerosis and insulin resistance

Jiansheng Huang, Huan Tao, Patricia G. Yancey, Zoe Leuthner, ... MacRae F. Linton

Objective

Oxidative stress contributes to the development of insulin resistance (IR) and atherosclerosis. Peroxidation of lipids produces reactive dicarbonyls such as Isolevuglandins (IsoLG) and malondialdehyde (MDA) that covalently bind plasma/cellular proteins, phospholipids, and DNA leading to altered function and toxicity. We examined whether scavenging reactive dicarbonyls with 5′-O-pentyl-pyridoxamine (PPM) protects against the development of IR and atherosclerosis in Ldlr−/− mice.

Methods

Male or female Ldlr−/− mice were fed a western diet (WD) for 16 weeks and treated with PPM versus vehicle alone. Plaque extent, dicarbonyl-lysyl adducts, efferocytosis, apoptosis, macrophage inflammation, and necrotic area were measured. Plasma MDA-LDL adducts and the in vivo and in vitro effects of PPM on the ability of HDL to reduce macrophage cholesterol were measured. Blood Ly6Chi monocytes and ex vivo 5-ethynyl-2′-deoxyuridine (EdU) incorporation into bone marrow CD11b+ monocytes and CD34+ hematopoietic stem and progenitor cells (HSPC) were also examined. IR was examined by measuring fasting glucose/insulin levels and tolerance to insulin/glucose challenge.

Results

PPM reduced the proximal aortic atherosclerosis by 48% and by 46% in female and male Ldlr−/− mice, respectively. PPM also decreased IR and hepatic fat and inflammation in male Ldlr−/− mice. Importantly, PPM decreased plasma MDA-LDL adducts and prevented the accumulation of plaque MDA- and IsoLG-lysyl adducts in Ldlr−/− mice. In addition, PPM increased the net cholesterol efflux capacity of HDL from Ldlr−/− mice and prevented both the in vitro impairment of HDL net cholesterol efflux capacity and apoAI crosslinking by MPO generated hypochlorous acid. Moreover, PPM decreased features of plaque instability including decreased proinflammatory M1-like macrophages, IL-1β expression, myeloperoxidase, apoptosis, and necrotic core. In contrast, PPM increased M2-like macrophages, Tregs, fibrous cap thickness, and efferocytosis. Furthermore, PPM reduced inflammatory monocytosis as evidenced by decreased blood Ly6Chi monocytes and proliferation of bone marrow monocytes and HSPC from Ldlr−/− mice.

Conclusions

PPM has pleotropic atheroprotective effects in a murine model of familial hypercholesterolemia, supporting the therapeutic potential of reactive dicarbonyl scavenging in the treatment of IR and atherosclerotic cardiovascular disease.

Scavenging dicarbonyls with 5′-O-pentyl-pyridoxamine increases HDL net cholesterol efflux capacity and attenuates atherosclerosis and insulin resistance

Jiansheng Huang, Huan Tao, Patricia G. Yancey, Zoe Leuthner, ... MacRae F. Linton

Objective

Oxidative stress contributes to the development of insulin resistance (IR) and atherosclerosis. Peroxidation of lipids produces reactive dicarbonyls such as Isolevuglandins (IsoLG) and malondialdehyde (MDA) that covalently bind plasma/cellular proteins, phospholipids, and DNA leading to altered function and toxicity. We examined whether scavenging reactive dicarbonyls with 5′-O-pentyl-pyridoxamine (PPM) protects against the development of IR and atherosclerosis in Ldlr−/− mice.

Methods

Male or female Ldlr−/− mice were fed a western diet (WD) for 16 weeks and treated with PPM versus vehicle alone. Plaque extent, dicarbonyl-lysyl adducts, efferocytosis, apoptosis, macrophage inflammation, and necrotic area were measured. Plasma MDA-LDL adducts and the in vivo and in vitro effects of PPM on the ability of HDL to reduce macrophage cholesterol were measured. Blood Ly6Chi monocytes and ex vivo 5-ethynyl-2′-deoxyuridine (EdU) incorporation into bone marrow CD11b+ monocytes and CD34+ hematopoietic stem and progenitor cells (HSPC) were also examined. IR was examined by measuring fasting glucose/insulin levels and tolerance to insulin/glucose challenge.

Results

PPM reduced the proximal aortic atherosclerosis by 48% and by 46% in female and male Ldlr−/− mice, respectively. PPM also decreased IR and hepatic fat and inflammation in male Ldlr−/− mice. Importantly, PPM decreased plasma MDA-LDL adducts and prevented the accumulation of plaque MDA- and IsoLG-lysyl adducts in Ldlr−/− mice. In addition, PPM increased the net cholesterol efflux capacity of HDL from Ldlr−/− mice and prevented both the in vitro impairment of HDL net cholesterol efflux capacity and apoAI crosslinking by MPO generated hypochlorous acid. Moreover, PPM decreased features of plaque instability including decreased proinflammatory M1-like macrophages, IL-1β expression, myeloperoxidase, apoptosis, and necrotic core. In contrast, PPM increased M2-like macrophages, Tregs, fibrous cap thickness, and efferocytosis. Furthermore, PPM reduced inflammatory monocytosis as evidenced by decreased blood Ly6Chi monocytes and proliferation of bone marrow monocytes and HSPC from Ldlr−/− mice.

Conclusions

PPM has pleotropic atheroprotective effects in a murine model of familial hypercholesterolemia, supporting the therapeutic potential of reactive dicarbonyl scavenging in the treatment of IR and atherosclerotic cardiovascular disease.

2021 impact factor: 8.568

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