Abstract
Circulating redox state changes, determined by the ratio of reduced/oxidized pairs of different metabolites, have been associated with metabolic diseases. However, the pathogenic contribution of these changes and whether they modulate normal tissue function is unclear. As alterations in hepatic gluconeogenesis and glycogen metabolism are hallmarks that characterize insulin resistance and type 2 diabetes, we tested whether imposed changes in the extracellular redox state could modulate these processes. Thus, primary hepatocytes were treated with different ratios of the following physiological extracellular redox couples: β-hydroxybutyrate (βOHB)/acetoacetate (Acoc), reduced glutathione (GSH)/oxidized glutathione (GSSG), and cysteine/cystine. Exposure to a more oxidized ratio via extracellular βOHB/Acoc, GSH/GSSG, and cysteine/cystine in hepatocytes from fed mice increased intracellular hydrogen peroxide without causing oxidative damage. On the other hand, addition of more reduced ratios of extracellular βOHB/Acoc led to increased NAD(P)H and maximal mitochondrial respiratory capacity in hepatocytes. Greater βOHB/Acoc ratios were also associated with decreased β-oxidation, as expected with enhanced lipogenesis. In hepatocytes from fasted mice, a more extracellular reduced state of βOHB/Acoc led to increased alanine-stimulated gluconeogenesis and enhanced glycogen synthesis capacity from added glucose. Thus, we demonstrated for the first time that the extracellular redox state regulates the major metabolic functions of the liver and involves changes in intracellular NADH, hydrogen peroxide, and mitochondrial respiration. Because redox state in the blood can be communicated to all metabolically sensitive tissues, this work confirms the hypothesis that circulating redox state may be an important regulator of whole body metabolism and contribute to alterations associated with metabolic diseases.
Highlights
Reduction/oxidation (“redox”) reactions involve the transfer of electrons between molecules, in which the reduced form of a molecule is oxidized after electron(s) are transferred to another molecule
We showed that alterations in the extracellular redox state, which are known to occur in diabetes [9], aging [19], cardiac dysfunction [20], and other disorders, can directly alter the internal redox state and the function of healthy murine hepatocytes
We propose that the mechanism by which a greater ratio of βOHB/Acoc allows for protection of liver function from oxidative damage caused by tert-butyl hydroperoxide (tBH) (Fig. 2A), changes in fatty acid oxidation (Fig. 4), and a greater mitochondrial respiration capacity (Fig. 3) may occur via the mitochondrial transhydrogenase (NNT)
Summary
Reduction/oxidation (“redox”) reactions involve the transfer of electrons between molecules, in which the reduced form of a molecule is oxidized after electron(s) are transferred to another molecule. Lactate (Lac) and pyruvate (Pyr) form a redox couple and their inter-conversion requires the NADH/NAD+ redox pair to mediate the transfer of electrons. These processes of electron transfer are involved in hundreds of vital reactions, can be catalyzed by enzymes, and a common byproduct of these reactions is the generation of reactive oxygen species (ROS). Despite the large number of redox pairs found inside the cell and their complex regulation, the NADH/NAD+ redox state can be estimated in the cytosol by measuring the Lac/Pyr ratio and inside the mitochondrial matrix by measuring β-hydroxybutyrate (βOHB)/acetoacetate (Acoc) ratios (review: [3]). The cysteine/cystine couple is not in equilibrium with the glutathione couple, and is typically more oxidized in all compartments [4]
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