Abstract
In addition to being the primary organ involved in redox cycling, the liver is one of the most highly innervated tissues in mammals. The interaction between hepatocytes and sympathetic, parasympathetic, and peptidergic nerve fibers through a variety of neurotransmitters and signaling pathways is recognized as being important in the regulation of hepatocyte function, liver regeneration, and hepatic fibrosis. However, less is known regarding the role of the sympathetic nervous system (SNS) in modulating the hepatic response to oxidative stress. Our aim was to investigate the role of the SNS in healthy and oxidatively stressed liver parenchyma. Mice treated with 6-hydroxydopamine hydrobromide were used to realize chemical sympathectomy. Carbon tetrachloride (CCl4) injection was used to induce oxidative liver injury. Sympathectomized animals were protected from CCl4 induced hepatic lipid peroxidation-mediated cytotoxicity and genotoxicity as assessed by 4-hydroxy-2-nonenal levels, morphological features of cell damage, and DNA oxidative damage. Furthermore, sympathectomy modulated hepatic inflammatory response induced by CCl4-mediated lipid peroxidation. CCl4 induced lipid peroxidation and hepatotoxicity were suppressed by administration of an α-adrenergic antagonist. We conclude that the SNS provides a permissive microenvironment for hepatic oxidative stress indicating the possibility that targeting the hepatic α-adrenergic signaling could be a viable strategy for improving outcomes in patients with acute hepatic injury.
Highlights
The liver is one of the most highly innervated tissues in mammals
There was no hepatic necrosis in saline- or 6-OHDA-treated mice treated with olive oil alone
Biochemical markers of liver injury, including aspartate aminotransferase (AST; 4,115 ± 1,755 versus 17, 830 ± 3, 078 IU/L, p < 0.0001), alanine aminotransferase (ALT; 7,809 ± 2,527 versus 15,519 ± 4,678, p = 0.0052), alkaline phosphatase (ALP; 56 ± 26 versus 128 ± 11, p = 0.0013), and lactate dehydrogenase (LDH; 11,139 ± 5,496 versus 28,764 ± 8,063, p = 0.0001) levels 24 h after CCl4 treatment were lower in serum from 6-OHDA-treated mice compared to the saline-treated group (Supplementary Data, Table S1)
Summary
The interaction between hepatocytes and sympathetic, parasympathetic, and peptidergic nerve fibers through a variety of neurotransmitters and signaling pathways is recognized as being important in the regulation of hepatocyte function and hepatic response to injury [1]. Sympathetic nervous system (SNS) transmission to hepatocytes occurs through release of norepinephrine and epinephrine as neurotransmitters from intrahepatic nerve endings and by delivery as hormones from adrenal glands. Hepatic monoamine oxidases catalyze oxidative deamination of catecholamines such as norepinephrine and epinephrine. During this process hydrogen peroxide (H2O2) is generated and further converted to water by glutathione peroxidase during which glutathione is utilized [6]. Intense physical work is known to increase sympathetic activity and ROS production in the rodent heart [12]. The knowledge that β-adrenergic stimulation is the main driver of ROS generation in mitochondria [13] has indicated the use of β-adrenergic receptor blockers to reduce oxidative stress in cardiac failure [14, 15]
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