Deficiency of metabolite sensing receptor HCA2 impairs the salutary effect of niacin in hemorrhagic shock

Kumar Subramani, Xiaogang Chu, Marie Warren, Mariah Lee, Sumin Lu, Nagendra Singh, Raghavan Pillai Raju

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2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)688-695
Number of pages8
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1865
Issue number3
DOIs
Publication statusPublished - Mar 1 2019

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Keywords

  • Hemorrhage
  • Immunometabolism
  • Nicotinic acid
  • Trauma

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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