Deletion of RAGE fails to prevent hepatosteatosis in obese mice due to impairment of other AGEs receptors and detoxifying systems

AbstractAdvanced glycation endproducts (AGEs) are involved in several diseases, including NAFLD and NASH. RAGE is the main receptor mediating the pro-inflammatory signalling induced by AGEs. Therefore, targeting of RAGE has been proposed for prevention of chronic inflammatory diseases. However, the role of RAGE in the development of NAFLD and NASH remains poorly understood. We thus aimed to analyse the effect of obesity on AGEs accumulation, AGE-receptors and AGE-detoxification, and whether the absence of RAGE might improve hepatosteatosis and inflammation, by comparing the liver of lean control, obese (LeptrDb−/−) and obese RAGE-deficient (RAGE−/− LeptrDb−/−) mice. Obesity induced AGEs accumulation and RAGE expression with hepatosteatosis and inflammation in LeptrDb−/−, compared to lean controls. Despite the genetic deletion of RAGE in the LeptrDb−/− mice, high levels of intrahepatic AGEs were maintained accompanied by decreased expression of the protective AGE-receptor-1, impaired AGE-detoxifying system glyoxalase-1, and increased expression of the alternative AGE-receptor galectin-3. We also found sustained hepatosteatosis and inflammation as determined by persistent activation of the lipogenic SREBP1c and proinflammatory NLRP3 signalling pathways. Thus, RAGE targeting is not effective in the prevention of NAFLD in conditions of obesity, likely due to the direct liver specific crosstalk of RAGE with other AGE-receptors and AGE-detoxifying systems.

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The Immune Tolerance Role of the HMGB1-RAGE Axis

Cells ◽

10.3390/cells10030564 ◽

2021 ◽

Vol 10 (3) ◽

pp. 564

Author(s):

Haruki Watanabe ◽

Myoungsun Son

Keyword(s):

Immune Responses ◽

Immune Tolerance ◽

Lupus Erythematosus ◽

Advanced Glycation Endproducts ◽

High Mobility ◽

Chromatin Binding ◽

Advanced Glycation ◽

Glycation Endproducts ◽

Extracellular Milieu

The disruption of the immune tolerance induces autoimmunity such as systemic lupus erythematosus and vasculitis. A chromatin-binding non-histone protein, high mobility group box 1 (HMGB1), is released from the nucleus to the extracellular milieu in particular environments such as autoimmunity, sepsis and hypoxia. Extracellular HMGB1 engages pattern recognition receptors, including Toll-like receptors (TLRs) and the receptor for advanced glycation endproducts (RAGE). While the HMGB1-RAGE axis drives inflammation in various diseases, recent studies also focus on the anti-inflammatory effects of HMGB1 and RAGE. This review discusses current perspectives on HMGB1 and RAGE’s roles in controlling inflammation and immune tolerance. We also suggest how RAGE heterodimers responding microenvironments functions in immune responses.

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Abstract 563: Mechanisms of VEGFR3-Dependent Pathological Lymphangiogenesis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.563 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Wang Min

Keyword(s):

Inflammatory Diseases ◽

Active Form ◽

Lymphatic Vessels ◽

Master Regulators ◽

Downstream Signaling ◽

Neonatal Skin ◽

Genetic Deletion ◽

Vasculogenesis And Angiogenesis ◽

Intracellular Mediators

Vascular remodeling, i.e., the growth and/or enlargement of both blood and lymphatic vessels, is tightly associated with inflammatory diseases, such as chronic airway inflammation, rheumatoid arthritis, inflammatory bowl disease, and chronic inflammatory skin psoriasis. The lymphatic system collects extravasated fluid, macromolecules, and immune cells from tissues and returns them to the blood circulation. While VEGFR2 and its ligand VEGF-A functions as master regulators of vasculogenesis and angiogenesis, VEGFR3 is critical for lymphangiogenesis. These conclusions are based on observations in genetically modified mice for VEGFR3 and its ligands. VEGFR3 is expressed on the blood and lymphatic endothelium during development, and is restricted to the lymphatics in the adult. Extensive studies have thus far focused on the role of VEGFR3 in lymphangiogenesis during development, however the function, regulation and intracellular mediators of the VEGFR3-dependent pathways in pathologic formation of lymphatic vessels during diseases remain poorly characterized. Our recent studies have identified two critical intracellular mediators, AIP1 and Bmx, in regulating VEGFR3 expression and activity. Genetic deletion of AIP1, a Ras-GAP protein, delays developmental lymphangiogenesis in neonatal skin and mesentery, and mounts weaker VEGF-C-induced cornea lymphangiogenesis. Deletion of Bmx, a non-receptor tyrosine kinase, has no effect on developmental lymphangiogenesis but blunts pathological lymphangiogenesis in mouse models. Mechanistically, AIP1 and Bmx sequentially regulate different steps during the VEGFR3 activation. AIP1 constitutively binds to VEGFR3 and enhances VEGFR3 endocytosis and stability. Bmx is not expressed in developmental lymphatics but is induced in response to pathological stimuli such as ischemia, and associates with an active form of VEGFR3 to regulate its downstream signaling without an effect on receptor phosphorylation. I will report the most recent progress as to how AIP1 and Bmx coordinately regulate VEGFR3-dependent lymphangiogenesis.

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Oxidative Stress and Adipocyte Biology: Focus on the Role of AGEs

Oxidative Medicine and Cellular Longevity ◽

10.1155/2015/534873 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 31

Author(s):

Florence Boyer ◽

Jennifer Baraka Vidot ◽

Alexis Guerin Dubourg ◽

Philippe Rondeau ◽

M. Faadiel Essop ◽

...

Keyword(s):

Oxidative Stress ◽

Adipose Tissue ◽

Advanced Glycation Endproducts ◽

Glycated Albumin ◽

Major Health Problem ◽

Glycation Endproducts ◽

Diabetes Progression ◽

The Impact ◽

Pathologic Processes

Diabetes is a major health problem that is usually associated with obesity, together with hyperglycemia and increased advanced glycation endproducts (AGEs) formation. Elevated AGEs elicit severe downstream consequences via their binding to receptors of AGEs (RAGE). This includes oxidative stress and oxidative modifications of biological compounds together with heightened inflammation. For example, albumin (major circulating protein) undergoes increased glycoxidation with diabetes and may represent an important biomarker for monitoring diabetic pathophysiology. Despite the central role of adipose tissue in many physiologic/pathologic processes, recognition of the effects of greater AGEs formation in this tissue is quite recent within the obesity/diabetes context. This review provides a brief background of AGEs formation and adipose tissue biology and thereafter discusses the impact of AGEs-adipocyte interactions in pathology progression. Novel data are included showing how AGEs (especially glycated albumin) may be involved in hyperglycemia-induced oxidative damage in adipocytes and its potential links to diabetes progression.

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Binding of CML-Modified as Well as Heat-Glycated β-lactoglobulin to Receptors for AGEs Is Determined by Charge and Hydrophobicity

International Journal of Molecular Sciences ◽

10.3390/ijms21124567 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4567 ◽

Cited By ~ 1

Author(s):

Hannah E. Zenker ◽

Malgorzata Teodorowicz ◽

Arifa Ewaz ◽

R.J. Joost van Neerven ◽

Huub F.J. Savelkoul ◽

...

Keyword(s):

Secondary Structure ◽

Tertiary Structure ◽

Glyoxylic Acid ◽

Native Page ◽

Galectin 3 ◽

Carboxymethyl Lysine ◽

Antigen Presenting ◽

Age Receptors ◽

Β Lactoglobulin

Intake of dietary advanced glycation end products (AGEs) is associated with inflammation-related health problems. Nε-carboxymethyl lysine (CML) is one of the best characterised AGEs in processed food. AGEs have been described as ligands for receptors present on antigen presenting cells. However, changes in protein secondary and tertiary structure also induce binding to AGE receptors. We aimed to discriminate the role of different protein modifications in binding to AGE receptors. Therefore, β-lactoglobulin was chemically modified with glyoxylic acid to produce CML and compared to β-lactoglobulin glycated with lactose. Secondary structure was monitored with circular dichroism, while hydrophobicity and formation of β-sheet structures was measured with ANS-assay and ThT-assay, respectively. Aggregation was monitored using native-PAGE. Binding to sRAGE, CD36, and galectin-3 was measured using inhibition ELISA. Even though no changes in secondary structure were observed in all tested samples, binding to AGE receptors increased with CML concentration of CML-modified β-lactoglobulin. The negative charge of CML was a crucial determinant for the binding of protein bound CML, while binding of glycated BLG was determined by increasing hydrophobicity. This shows that sRAGE, galectin-3, and CD36 bind to protein bound CML and points out the role of negatively charged AGEs in binding to AGE receptors.

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The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases

Clinical Science ◽

10.1042/cs20140683 ◽

2015 ◽

Vol 128 (12) ◽

pp. 839-861 ◽

Cited By ~ 131

Author(s):

Dionne E.M. Maessen ◽

Coen D.A. Stehouwer ◽

Casper G. Schalkwijk

Keyword(s):

Advanced Glycation Endproducts ◽

Treatment Strategies ◽

Glyoxalase System ◽

Dicarbonyl Compound ◽

Glycation Endproducts ◽

Age Related ◽

Key Enzyme ◽

The Central Nervous System ◽

New Treatment

The formation and accumulation of advanced glycation endproducts (AGEs) are related to diabetes and other age-related diseases. Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is the major precursor in the formation of AGEs. MGO is mainly formed as a byproduct of glycolysis. Under physiological circumstances, MGO is detoxified by the glyoxalase system into D-lactate, with glyoxalase I (GLO1) as the key enzyme in the anti-glycation defence. New insights indicate that increased levels of MGO and the major MGO-derived AGE, methylglyoxal-derived hydroimidazolone 1 (MG-H1), and dysfunctioning of the glyoxalase system are linked to several age-related health problems, such as diabetes, cardiovascular disease, cancer and disorders of the central nervous system. The present review summarizes the mechanisms through which MGO is formed, its detoxification by the glyoxalase system and its effect on biochemical pathways in relation to the development of age-related diseases. Although several scavengers of MGO have been developed over the years, therapies to treat MGO-associated complications are not yet available for application in clinical practice. Small bioactive inducers of GLO1 can potentially form the basis for new treatment strategies for age-related disorders in which MGO plays a pivotal role.

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