Refine
Year of publication
Document Type
- Article (47)
- Postprint (11)
- Conference Proceeding (2)
- Other (1)
- Preprint (1)
Language
- English (62)
Is part of the Bibliography
- yes (62) (remove)
Keywords
- NASH (6)
- inflammation (6)
- oxidative stress (6)
- cell-based assay (5)
- NAFLD (4)
- cholesterol (4)
- BoNT (2)
- BoNT/B uptake (2)
- Botulinum neurotoxin (2)
- E-2 (2)
- FGF21 (2)
- IL-8 transcription (2)
- PUFA (2)
- RRR (2)
- VGCC (2)
- accumulation (2)
- botulinum toxin (2)
- cancer cachexia (2)
- cell-based in vitro assay (2)
- cyclooxygenase (2)
- disease (2)
- eicosanoids (2)
- endurance exercise (2)
- erythropoiesis (2)
- expression (2)
- genetically modified BoNT (2)
- glucose intolerance (2)
- hepatic steatosis (2)
- induced pluripotent stem cells (2)
- insulin (2)
- insulin-resistance (2)
- kupffer cells (2)
- lipid peroxidation (2)
- mice lacking (2)
- motor neurons (2)
- muscarinic acetylcholine receptor (2)
- neurotoxins (2)
- non-alcoholic fatty liver disease (NAFLD) (2)
- nonalcoholic steatohepatthis (2)
- polyenoic fatty acids (2)
- rat hepatocytes (2)
- replacement (2)
- suppress VLDL secretion (2)
- tetanus toxin (2)
- type 2 diabetes (2)
- voltage-dependent calcium channels (2)
- white adipose tissue (2)
- Akt pathway (1)
- Aryl-hydrocarbon receptor (1)
- Botulinum toxin (1)
- CRISPR editing validation (1)
- Cyp2b1 (1)
- Dietary Cholesterol (1)
- Endocrine disruption (1)
- Epigenetics (1)
- FTY720 (1)
- Fetal programming (1)
- IB (1)
- Insulin signalling (1)
- IκB (1)
- Kupffer Cells (1)
- M1/M2 differentiation (1)
- Monocyte (1)
- NAFLD/MAFLD (1)
- NF-?B (1)
- NF-B (1)
- NF-κB (1)
- Non-alcoholic fatty liver disease (1)
- Nonalcoholic Fatty Liver Disease (NAFLD) (1)
- Nonalcoholic Steatohepatitis (NASH) (1)
- PGC1 alpha (1)
- Palmitate (1)
- Prostaglandin receptor EP4 (1)
- S1P receptors (1)
- SLC13A5 (1)
- Signal transduction (1)
- Sphingolipids (1)
- Sphingosine 1-phosphate (1)
- TLR signaling (1)
- Thyroid hormone (1)
- Tumor necrosis factor alpha (1)
- Typical Western Diet (1)
- UDP-glucuronosyltransferase (1)
- Xenobesity (1)
- assessment (1)
- constitutive androstane receptor (1)
- copy number analyses (1)
- cytokine (1)
- cytokines (1)
- eNOS (1)
- enzyme induction (1)
- fatty liver (1)
- homologous recombination deficiency (1)
- homology-directed repair (1)
- interleukin-8 (1)
- liver toxicity (1)
- mPGES (1)
- macrophage (1)
- macrophages (1)
- metabolic syndrome (1)
- metabolism (1)
- mixtures (1)
- mouse lethality assay (1)
- obesity (1)
- potency (1)
- potency assessment (1)
- pregnane X-receptor (1)
- prostaglandin E-2 (1)
- prostaglandin receptor (1)
- signal transduction (1)
- suppressor of cytokine signaling (SOCS) (1)
- triazole fungicides (1)
- type 2 diabetes (T2DM) (1)
- type II diabetes (T2DM) (1)
- vicious cycle (1)
Mammalian arachidonic acid lipoxygenases (ALOXs) have been implicated in cell differentiation and in the pathogenesis of inflammation. The mouse genome involves seven functional Alox genes and the encoded enzymes share a high degree of amino acid conservation with their human orthologs. There are, however, functional differences between mouse and human ALOX orthologs. Human ALOX15B oxygenates arachidonic acid exclusively to its 15-hydroperoxy derivative (15S-HpETE), whereas 8S-HpETE is dominantly formed by mouse Alox15b. The structural basis for this functional difference has been explored and in vitro mutagenesis humanized the reaction specificity of the mouse enzyme. To explore whether this mutagenesis strategy may also humanize the reaction specificity of mouse Alox15b in vivo, we created Alox15b knock-in mice expressing the arachidonic acid 15-lipoxygenating Tyr603Asp+His604Val double mutant instead of the 8-lipoxygenating wildtype enzyme. These mice are fertile, display slightly modified plasma oxylipidomes and develop normally up to an age of 24 weeks. At later developmental stages, male Alox15b-KI mice gain significantly less body weight than outbred wildtype controls, but this effect was not observed for female individuals. To explore the possible reasons for the observed gender-specific growth arrest, we determined the basic hematological parameters and found that aged male Alox15b-KI mice exhibited significantly attenuated red blood cell parameters (erythrocyte counts, hematocrit, hemoglobin). Here again, these differences were not observed in female individuals. These data suggest that humanization of the reaction specificity of mouse Alox15b impairs the functionality of the hematopoietic system in males, which is paralleled by a premature growth arrest.
Metabolic derangement with poor glycemic control accompanying overweight and obesity is associated with chronic low-grade inflammation and hyperinsulinemia. Macrophages, which present a very heterogeneous population of cells, play a key role in the maintenance of normal tissue homeostasis, but functional alterations in the resident macrophage pool as well as newly recruited monocyte-derived macrophages are important drivers in the development of low-grade inflammation. While metabolic dysfunction, insulin resistance and tissue damage may trigger or advance pro-inflammatory responses in macrophages, the inflammation itself contributes to the development of insulin resistance and the resulting hyperinsulinemia. Macrophages express insulin receptors whose downstream signaling networks share a number of knots with the signaling pathways of pattern recognition and cytokine receptors, which shape macrophage polarity. The shared knots allow insulin to enhance or attenuate both pro-inflammatory and anti-inflammatory macrophage responses. This supposedly physiological function may be impaired by hyperinsulinemia or insulin resistance in macrophages. This review discusses the mutual ambiguous relationship of low-grade inflammation, insulin resistance, hyperinsulinemia and the insulin-dependent modulation of macrophage activity with a focus on adipose tissue and liver.