Deficiency of metabolite sensing receptor HCA2 impairs the salutary effect of niacin in hemorrhagic shock
| Autor: | Mariah Lee, Raghavan Raju, Kumar Subramani, Marie Warren, Xiaogang Chu, Sumin Lu, Nagendra Singh |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Metabolite Inflammation Shock Hemorrhagic Pharmacology Niacin Permeability Article Receptors G-Protein-Coupled Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Animals Intestinal Mucosa Receptor Molecular Biology Nicotinamide mononucleotide Mice Knockout biology Sirtuin 1 Chemistry Myocardium digestive oral and skin physiology food and beverages 030208 emergency & critical care medicine NAD Survival Analysis Mice Inbred C57BL 030104 developmental biology biology.protein Molecular Medicine Protein deacetylase NAD+ kinase medicine.symptom NADP Signal Transduction |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1865:688-695 |
| ISSN: | 0925-4439 |
| Popis: | Inflammation and cellular energetics play critical roles in organ dysfunction following hemorrhagic shock. Recent studies suggest a putative role for sirtuin 1 (SIRT1) in potentiating mitochondrial function and improving organ function following hemorrhagic shock in animal models. SIRT1 is an NAD+ dependent protein deacetylase and increased availability of NAD+ has been shown to augment SIRT1 activity. As niacin is a precursor of NAD+, in this study, we tested whether niacin can improve survival following hemorrhagic shock. However niacin also mediates its biological action by binding to its receptor, hydroxyl-carboxylic acid receptor 2 (HCA2 or Gpr109a); so we examined whether the effect of niacin is mediated by binding to Gpr109a or by increasing NAD+ availability. We found that niacin administered intravenously to rats subjected to hemorrhagic injury (HI) in the absence of fluid resuscitation resulted in a significantly prolonged duration of survival. However, treatment of rats with similar doses of nicotinamide mononucleotide (NMN), a precursor to NAD+ that does not bind Gpr109a, did not extend survival following HI. The duration of survival due to niacin treatment was significantly reduced in Gpr109a−/− mice subjected to HI. These experiments demonstrated that the Gpr109a receptor-mediated pathway contributed significantly to niacin mediated salutary effect. Further studies showed improvement in markers of cellular energetics and attenuation of inflammatory response with niacin treatment. In conclusion, we report that Gpr109a-dependent signalling is important in restoring cellular energetics and immunometabolism following hemorrhagic shock. |
| Databáze: | OpenAIRE |
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