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1.
Adv Sci (Weinh) ; : e2308461, 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38884133

ABSTRACT

Type 1 diabetes (T1D) is a chronic disease characterized by self-destruction of insulin-producing pancreatic ß cells by cytotoxic T cell activity. However, the pathogenic mechanism of T cell infiltration remains obscure. Recently, tissue-resident memory T (TRM) cells have been shown to contribute to cytotoxic T cell recruitment. TRM cells are found present in human pancreas and are suggested to modulate immune homeostasis. Here, the role of TRM cells in the development of T1D is investigated. The presence of TRM cells in pancreatic islets is observed in non-obese diabetic (NOD) mice before T1D onset. Mechanistically, elevated fatty acid-binding protein 4 (FABP4) potentiates the survival and alarming function of TRM cells by promoting fatty acid utilization and C-X-C motif chemokine 10 (CXCL10) secretion, respectively. In NOD mice, genetic deletion of FABP4 or depletion of TRM cells using CD69 neutralizing antibodies resulted in a similar reduction of pancreatic cytotoxic T cell recruitment, a delay in diabetic incidence, and a suppression of CXCL10 production. Thus, targeting FABP4 may represent a promising therapeutic strategy for T1D.

2.
Adv Sci (Weinh) ; 9(20): e2200742, 2022 07.
Article in English | MEDLINE | ID: mdl-35524581

ABSTRACT

Dysfunctional triglyceride-very low-density lipoprotein (TG-VLDL) metabolism is linked to metabolic-associated fatty liver disease (MAFLD); however, the underlying cause remains unclear. The study shows that hepatic E3 ubiquitin ligase murine double minute 2 (MDM2) controls MAFLD by blocking TG-VLDL secretion. A remarkable upregulation of MDM2 is observed in the livers of human and mouse models with different levels of severity of MAFLD. Hepatocyte-specific deletion of MDM2 protects against high-fat high-cholesterol diet-induced hepatic steatosis and inflammation, accompanied by a significant elevation in TG-VLDL secretion. As an E3 ubiquitin ligase, MDM2 targets apolipoprotein B (ApoB) for proteasomal degradation through direct protein-protein interaction, which leads to reduced TG-VLDL secretion in hepatocytes. Pharmacological blockage of the MDM2-ApoB interaction alleviates dietary-induced hepatic steatohepatitis and fibrosis by inducing hepatic ApoB expression and subsequent TG-VLDL secretion. The effect of MDM2 on VLDL metabolism is p53-independent. Collectively, these findings suggest that MDM2 acts as a negative regulator of hepatic ApoB levels and TG-VLDL secretion in MAFLD. Inhibition of the MDM2-ApoB interaction may represent a potential therapeutic approach for MAFLD treatment.


Subject(s)
Apolipoproteins B , Fatty Liver , Lipoproteins, VLDL , Liver , Obesity , Proto-Oncogene Proteins c-mdm2 , Triglycerides , Animals , Apolipoproteins B/metabolism , Fatty Liver/etiology , Fatty Liver/metabolism , Humans , Lipoproteins, VLDL/metabolism , Liver/metabolism , Mice , Obesity/complications , Proteolysis , Proto-Oncogene Proteins c-mdm2/metabolism , Triglycerides/metabolism
3.
JCI Insight ; 6(7)2021 04 08.
Article in English | MEDLINE | ID: mdl-33690220

ABSTRACT

Both innate and adaptive immune cells are critical players in autoimmune destruction of insulin-producing ß cells in type 1 diabetes. However, the early pathogenic events triggering the recruitment and activation of innate immune cells in islets remain obscure. Here we show that circulating fatty acid binding protein 4 (FABP4) level was significantly elevated in patients with type 1 diabetes and their first-degree relatives and positively correlated with the titers of several islet autoantibodies. In nonobese diabetic (NOD) mice, increased FABP4 expression in islet macrophages started from the neonatal period, well before the occurrence of overt diabetes. Furthermore, the spontaneous development of autoimmune diabetes in NOD mice was markedly reduced by pharmacological inhibition or genetic ablation of FABP4 or adoptive transfer of FABP4-deficient bone marrow cells. Mechanistically, FABP4 activated innate immune responses in islets by enhancing the infiltration and polarization of macrophages to proinflammatory M1 subtype, thus creating an inflammatory milieu required for activation of diabetogenic CD8+ T cells and shift of CD4+ helper T cells toward Th1 subtypes. These findings demonstrate FABP4 as a possible early mediator for ß cell autoimmunity by facilitating crosstalk between innate and adaptive immune cells, suggesting that pharmacological inhibition of FABP4 may represent a promising therapeutic strategy for autoimmune diabetes.


Subject(s)
Diabetes Mellitus, Type 1/immunology , Fatty Acid-Binding Proteins/blood , Fatty Acid-Binding Proteins/immunology , Macrophages/immunology , Adult , Animals , Autoantibodies/blood , Benzothiazoles , Bone Marrow Transplantation , Carbocyanines , Diabetes Mellitus, Experimental/immunology , Diabetes Mellitus, Experimental/therapy , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 1/pathology , Diabetes Mellitus, Type 1/therapy , Fatty Acid-Binding Proteins/genetics , Fatty Acid-Binding Proteins/metabolism , Female , Humans , Islets of Langerhans/immunology , Islets of Langerhans/pathology , Macrophages/pathology , Male , Mice, Inbred NOD , Mice, Mutant Strains , Middle Aged , T-Lymphocytes/immunology
4.
Clin Sci (Lond) ; 129(7): 547-59, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26186740

ABSTRACT

Clinical evidence shows that circulating levels of adipocyte fatty-acid-binding protein (A-FABP) are elevated in patients with diabetes and closely associated with ischaemic heart disease. Patients with diabetes are more susceptible to myocardial ischaemia/reperfusion (MI/R) injury. The experiments in the present study investigated the role of A-FABP in MI/R injury with or without diabetes. Non-diabetic and diabetic (streptozotocin-induced) A-FABP knockout and wild-type mice were subjected to MI/R or sham intervention. After MI/R, A-FABP knockout mice exhibited reductions in myocardial infarct size, apoptotic index, oxidative and nitrative stress, and inflammation. These reductions were accompanied by an improved left ventricular function compared with the relative controls under non-diabetic or diabetic conditions. After diabetes induction, A-FABP knockout mice exhibited a preserved cardiac function compared with that in wild-type mice. Endothelial cells, but not cardiomyocytes, were identified as the most likely source of cardiac A-FABP. Cardiac and circulating A-FABP levels were significantly increased in mice with diabetes or MI/R. Diabetes-induced superoxide anion production was significantly elevated in wild-type mice, but diminished in A-FABP knockout mice, and this elevation contributed to the exaggeration of MI/R-induced cardiac injury. Phosphorylation of endothelial nitric oxide synthase (eNOS) and production of nitric oxide (NO) were enhanced in both diabetic and non-diabetic A-FABP knockout mice after MI/R injury, but diminished in wild-type mice. The beneficial effects of A-FABP deficiency on MI/R injury were abolished by the NOS inhibitor N(G)-nitro-L-arginine methyl ester. Thus, A-FABP deficiency protects mice against MI/R-induced and/or diabetes-induced cardiac injury at least partially through activation of the eNOS/NO pathway and reduction in superoxide anion production.


Subject(s)
Diabetes Mellitus/metabolism , Fatty Acid-Binding Proteins/genetics , Fatty Acid-Binding Proteins/physiology , Myocardial Ischemia/therapy , Myocardium/pathology , Animals , Anions , Apoptosis , Blood Pressure , Endothelium, Vascular/metabolism , Immunohistochemistry , Inflammation , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Fluorescence , Myocardial Reperfusion Injury/physiopathology , Oxidative Stress , Reperfusion Injury , Superoxides/metabolism
5.
Nutr Metab (Lond) ; 7: 67, 2010 Aug 24.
Article in English | MEDLINE | ID: mdl-20735814

ABSTRACT

BACKGROUND: Macrophage infiltration in adipose tissue together with the aberrant production of pro-inflammatory cytokines has been identified as the key link between obesity and its related metabolic disorders. This study aims to isolate bioactive ingredients from the traditional Chinese herb Radix Astragali (Huangqi) that alleviate obesity-induced metabolic damage through inhibiting inflammation. METHODS: Active fraction (Rx) that inhibits pro-inflammatory cytokine production was identified from Radix Astragali by repeated bioactivity-guided high-throughput screening. Major constituents in Rx were identified by column chromatography followed by high-performance liquid chromatography (HPLC) and mass-spectrometry. Anti-diabetic activity of Rx was evaluated in db/db mice. RESULTS: Treatment with Rx, which included calycosin-7-ß-D-glucoside (0.9%), ononin (1.2%), calycosin (4.53%) and formononetin (1.1%), significantly reduced the secretion of pro-inflammatory cytokines (TNF-α, IL-6 and MCP-1) in human THP-1 macrophages and lipopolysaccharide (LPS)-induced activation of NF-κB in mouse RAW-Blue macrophages in a dose-dependent manner. Chronic administration of Rx in db/db obese mice markedly decreased the levels of both fed and fasting glucose, reduced serum triglyceride, and also alleviated insulin resistance and glucose intolerance when compared to vehicle-treated controls. The mRNA expression levels of inflammatory cell markers CD68 and F4/80, and cytokines MCP-1, TNF-α and IL-6 were significantly reduced in epididymal adipose tissue while the alternatively activated macrophage marker arginase I was markedly increased in the Rx-treated mice. CONCLUSION: These findings suggest that suppression of the inflammation pathways in macrophages represents a valid strategy for high-throughput screening of lead compounds with anti-diabetic and insulin sensitizing properties, and further support the etiological role of inflammation in the pathogenesis of obesity-related metabolic disorders.

6.
Expert Rev Endocrinol Metab ; 3(1): 29-41, 2008 Jan.
Article in English | MEDLINE | ID: mdl-30743783

ABSTRACT

Obesity is an important risk factor for a cluster of metabolic and cardiovascular diseases, including insulin resistance, Type 2 diabetes, nonalcoholic fatty liver disease and atherosclerosis. Systemic low-grade inflammation, characterized by elevated circulating concentrations of proinflammatory factors, has recently been proposed to be a key mediator that links obesity with its medical complications. Adipose tissue is now recognized as the major contributor to systemic inflammation associated with obesity. As obesity develops, adipose tissue is infiltrated with activated macrophages. The 'inflamed' adipose tissue secretes a large number of proinflammatory adipokines and/or cytokines, which can act either in an autocrine manner to perpetuate local inflammation or in an endocrine manner to induce insulin resistance and endothelial dysfunction. In this review, we summarize recent advances in several newly identified adipose tissue-derived inflammatory factors, with the focus on lipocalin-2 and adipocyte fatty acid-binding protein (A-FABP). Both lipocalin-2 and A-FABP possess lipid-binding properties and are important integrators of metabolic and inflammatory pathways. A growing body of evidence from experimental, epidemiological and genetic studies suggests that both lipocalin-2 and A-FABP represent a novel class of serum biomarkers for risk prediction and therapeutic intervention of obesity-related medical complications.

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