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

TY - JOUR

T1 - Low cerebral energy metabolism in hepatic encephalopathy reflects low neuronal energy demand. Role of ammonia-induced increased GABAergic tone

AU - Sørensen, Michael

AU - Walls, Anne Byriel

AU - Dam, Gitte

AU - Bak, Lasse Kristoffer

AU - Andersen, Jens Velde

AU - Ott, Peter

AU - Vilstrup, Hendrik

AU - Schousboe, Arne

PY - 2022/10/1

Y1 - 2022/10/1

N2 - 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.

AB - 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.

KW - Ammonia/metabolism

KW - Brain/metabolism

KW - Energy Metabolism

KW - Glutamine/metabolism

KW - Hepatic Encephalopathy/etiology

KW - Humans

KW - Hyperammonemia/metabolism

KW - Neurons/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85132863219&partnerID=8YFLogxK

U2 - 10.1016/j.ab.2022.114766

DO - 10.1016/j.ab.2022.114766

M3 - Journal article

C2 - 35654134

SN - 0003-2697

VL - 654

JO - Analytical Biochemistry

JF - Analytical Biochemistry

M1 - 114766

ER -