Low cerebral energy metabolism in hepatic encephalopathy reflects low neuronal energy demand. Role of ammonia-induced increased GABAergic tone

• Published in: Analytical biochemistry Vol. 654; p. 114766
• Main Authors: Sørensen, Michael, Walls, Anne Byriel, Dam, Gitte, Bak, Lasse Kristoffer, Andersen, Jens Velde, Ott, Peter, Vilstrup, Hendrik, Schousboe, Arne
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2022
• Subjects: Cell cultures; Cerebral energy metabolism; Functional imaging; Hyperammonemia; Isotopes; Cerebral energy metabolism; Cell cultures; Isotopes; Hyperammonemia; Functional imaging
• ISSN: 0003-2697; 1096-0309
• DOI: 10.1016/j.ab.2022.114766

Hepatic encephalopathy (HE) is a frequent and devastating but generally reversible neuropsychiatric complication secondary to chronic and acute liver failure. During HE, brain energy metabolism is markedly reduced and it remains unclear whether this is due to external or internal energy supply limitations, or secondary to depressed neuronal cellular functions - and if so, which mechanisms that are in play. The extent of deteriorated cerebral function correlates to blood ammonia levels but the metabolic link to ammonia is not clear. Early studies suggested that high levels of ammonia inhibited key tricarboxylic acid (TCA) cycle enzymes thus limiting mitochondrial energy production and oxygen consumption; however, later studies by us and others showed that this is not the case in vivo. Here, based on a series of translational studies from our group, we advocate the view that the low cerebral energy metabolism of HE is likely to be caused by neuronal metabolic depression due to an elevated GABAergic tone rather than by restricted energy availability. The increased GABAergic tone seems to be secondary to synthesis of large amounts of glutamine in astrocytes for detoxification of ammonia with the glutamine acting as a precursor for elevated neuronal synthesis of vesicular GABA. [Display omitted] •Cerebral blood flow and oxygen metabolism are decreased during hepatic encephalopathy with hyperammonemia.•In animals and cell cultures, hyperammonia does not inhibit energy metabolism.•Hyperammonia increases flux of astrocytic glutamine into neuronal GABA.•Increased GABA is most likely the cause of decreased brain oxygen demand during hepatic enephalopathy