Abstract
The pathogenesis of hepatic encephalopathy (HE) in cirrhosis is multifactorial and ammonia is thought to play a key role. Astroglial dysfunction is known to be present in HE. Astrocytes are extensively connected by gap junctions formed of connexins, which also exist as functional hemichannels allowing exchange of molecules between the cytoplasm and the extracellular milieu. The astrocyte‐neuron lactate shuttle hypothesis suggests that neuronal activity is fueled (at least in part) by lactate provided by neighboring astrocytes. We hypothesized that in HE, astroglial dysfunction could impair metabolic communication between astrocytes and neurons. In this study, we determined whether hyperammonemia leads to hemichannel dysfunction and impairs lactate transport in the cerebral cortex using rat models of HE (bile duct ligation [BDL] and induced hyperammonemia) and also evaluated the effect of ammonia‐lowering treatment (ornithine phenylacetate [OP]). Plasma ammonia concentration in BDL rats was significantly reduced by OP treatment. Biosensor recordings demonstrated that HE is associated with a significant reduction in both tonic and hypoxia‐induced lactate release in the cerebral cortex, which was normalized by OP treatment. Cortical dye loading experiments revealed hemichannel dysfunction in HE with improvement following OP treatment, while the expression of key connexins was unaffected. Conclusion: The results of the present study demonstrate that HE is associated with central nervous system hemichannel dysfunction, with ammonia playing a key role. The data provide evidence of a potential neuronal energy deficit due to impaired hemichannel‐mediated lactate transport between astrocytes and neurons as a possible mechanism underlying pathogenesis of HE. (Hepatology 2017;65:1306‐1318)
Highlights
H epatic encephalopathy (HE) is a serious neuropsychiatric complication that is associated with liver dysfunction and is diagnosed when other known brain disorders are excluded.[1]
P values indicate differences between the responses recorded in the absence and presence of CBX. (C) Left: Summary data illustrating the effect of 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) (200 lM) on the release of lactate facilitated in response to 0 [Ca21]e in cortical slices of sham-operated, bile duct ligation (BDL), HA, and BDL-ornithine phenylacetate (OP) treated rats
Astrocytes represent an important source of lactate, which contributes to the extracellular pool of readily available metabolic substrates taken up by neurons to fuel their activity.[31] it was thought previously that lactate transport across the cell membranes was achieved solely through the operation of monocarboxylate transporter (MCT), a recent study[13] demonstrated that connexin hemichannels are important conduits of lactate release
Summary
H epatic encephalopathy (HE) is a serious neuropsychiatric complication that is associated with liver dysfunction and is diagnosed when other known brain disorders are excluded.[1]. HEPATOLOGY published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases. Potential conflict of interest: Rajiv Jalan has collaborated with Ocera and Takeda, consults with Ocera, and has received speaking fees from Norgine He is the inventor of OCR-002, which has been patented by UCL and licensed to Ocera Therapeutics. It remains unknown whether significant changes in brain lactate metabolism develop in conditions of long-term central nervous system exposure to increased ammonia concentrations, such as that seen during chronic liver disease or HE
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