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

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, hydroxylcarboxylic acid receptor 2 (HCA2 or Gpr109a); so we further asked 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 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 Gpr109a receptormediated 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.

A Combination Treatment Strategy for Hemorrhagic Shock in a Rat Model Modulates Autophagy

“…We also observed prolonged survival following HI when the rats were treated with niacin (15). Niacin metabolizes to produce NAD + , increases SIRT1 activity and enhance mitochondrial function (16).…”

“…We recently reported in separate papers that niacin, dichloroacetate, and resveratrol have salutary effect in hemorrhagic shock when administered individually at 10-25 mg/Kg dose each (5,6,15). All three compounds directly or indirectly potentiate mitochondrial function and autophagy.…”

“…The three compounds, resveratrol, DCA and niacin, agents that are known to enhance autophagy and mitochondria function (5,6,15,(17)(18)(19)(20)(21)(22), were found to have optimal effect when used at a dose of 10-25 mg/Kg body weight in the rats. We hypothesized that a combinatorial formula that collectively promotes survival will decrease the dose of individual compounds toward improving survival after HI.…”

Juvenile Plasma Factors Improve Organ Function and Survival following Injury by Promoting Antioxidant Response

“…Animal studies were conducted as per the protocol approved by the Institutional Animal Use and Care committee at the Augusta University. Hemorrhagic shock was induced as described before [ 25 ]. Briefly 60% blood volume was removed in 45 minutes through femoral artery, to induce hypovolemic shock (Mean arterial pressure: 30-35 mm Hg) and this MAP was maintained for another 45 minutes (shock period).…”

“…Immunoblotting procedures were performed as we described previously [ 25 ]. Briefly, tissues or cells were homogenized in the lysis buffer.…”