Inhibition of in vitro CO2 production and lipid synthesis by 2-hydroxybutyric acid in rat brain

Abstract

Abstract2-Hydroxybutyric acid appears at high concentrations in situations related to deficient energy metabolism (e.g., birth asphyxia) and also in inherited metabolic diseases affecting the central nervous system during neonatal development, such as cerebral lactic acidosis, glutaric aciduria type II, dihydrolipoyl dehydrogenase (E 3 ) deficiency, and propionic acidemia. The present study was carried out to determine the effect of 2-hydroxybutyric acid at various concentrations (1-10 mM) on CO 2 production and lipid synthesis from labeled substrates in cerebral cortex of 30-day-old Wistar rats in vitro. CO 2 production was significantly inhibited (30-70%) by 2-hydroxybutyric acid in cerebral cortex prisms, in total homogenates and in the mitochondrial fraction. We also demonstrated a significant inhibition of lipid synthesis (20-45%) in cerebral cortex prisms and total homogenates in the presence of 2-hydroxybutyric acid. However, no inhibition of lipid synthesis occurred in homogenates free of nuclei and mitochondria. The results indicate an impairment of mitochondrial energy metabolism caused by 2-hydroxybutyric acid, a fact that may secondarily lead to reduction of lipid synthesis. It is possible that these findings may be associated with the neuropathophysiology of the situations where 2-hydroxybutyric acid is accumulated.

α-Hydroxybutyrate Is an Early Biomarker of Insulin Resistance and Glucose Intolerance in a Nondiabetic Population

“…These increases may be due to the effect of the redox imbalance on the directionality of the dehydrogenases that reduce/oxidize these keto acids ( Figure 7 ). In addition, α-HB has also been observed to be elevated in T2D subjects and animal models of T2D, as well as in severe lactic acidosis and ketoacidosis [25], [27], [30], [31], [32], [33], [34]. Interestingly, in normal subjects and T2D patients, it has been shown that restoration of the NADH/NAD + redox balance by glutathione infusion therapy resulted in improvement of insulin sensitivity and β-cell function in normal subjects and in T2D patients [35].…”

Metabonomic phenotype and identification of “heart blood stasis obstruction pattern” and “qi and yin deficiency pattern” of myocardial ischemia rat models

“…Consequently, energy consumption decreased. High plasma levels of 2-hydroxybutanoic acid in the QY also had a relationship with energy deficiency [22] . Additionally, 3-hydroxybutanoic acid was the intermediate product of FFA oxygenolysis in the liver and was the energy source for tissues excluding the liver.…”

The role of oxidative damage in the neuropathology of organic acidurias: Insights from animal studies

“…Despite the major involvement of the CNS, re£ected by signi¢cant brain structural abnormalities (Brismar and Ozand 1994;K˛lker et al 2002a), the pathophysiology of the neurological dysfunction is poorly established in these disorders. However, in the last few years the contributions of mitochondrial dysfunction, excitotoxicity and oxidative stress have been documented as probable underlying mechanisms of brain damage in a number of organic acidurias (Bridi et al 2003;Brusque et al 2001Brusque et al , 2002da Silva et al 2004;de Assis et al 2003;de Oliveira Marques et al 2003;Flott-Rahmel et al 1997;Fontella et al 2000Fontella et al , 2002Frizzo et al 2004;Ho¡mann and Zschocke 1999;K˛lker et al 1999, 2001a,b, 2002bLatini et al 2002Latini et al , 2003aMoyano et al 1997;Porciuncula et al 2000;Sgaravatti et al 2003;Silva et al 2001;Ullrich et al 1999;Wajner and Coelho 1997). We review here the latest developments and the present knowledge of the potential role of oxidative stress in some organic acidurias, with attention focused on the neuropathology of these disorders.…”