{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T20:14:43Z","timestamp":1785269683032,"version":"3.55.0"},"reference-count":65,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T00:00:00Z","timestamp":1594857600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002261","name":"Russian Foundation for Basic Research","doi-asserted-by":"publisher","award":["18-015-00106"],"award-info":[{"award-number":["18-015-00106"]}],"id":[{"id":"10.13039\/501100002261","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministerio de Ciencia e Innovaci\u00f3n - Instituto de Salud Carlos III co-funded with European Regional Development Funds (ERDF) and Fundaci\u00f3n Ram\u00f3n Areces.","award":["FIS PI18\/00150"],"award-info":[{"award-number":["FIS PI18\/00150"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: The relationship between liver disease and neuropathology in hepatic encephalopathy is well known, but the genesis of encephalopathy in liver failure is yet to be elucidated. Conceptually, the main cause of hepatic encephalopathy is the accumulation of brain ammonia due to impaired liver detoxification function or occurrence of portosystemic shunt. Yet, as well as taking up toxic ammonia, the liver also produces vital metabolites that ensure normal cerebral function. Given this, for insight into how perturbations in the metabolic capacity of the liver may be related to brain pathology, it is crucial to understand the extent of ammonia-related changes in the hepatic metabolism that provides respiratory fuel for the brain, a deficiency of which can give rise to encephalopathy. Methods: Hepatic encephalopathy was induced in starved rats by injection of ammonium acetate. Ammonia-induced toxicity was evaluated by plasma and freeze-clamped liver and brain energy metabolites, and mitochondrial, cytoplasmic, and microsomal gluconeogenic enzymes, including mitochondrial ketogenic enzymes. Parameters of oxidative phosphorylation were recorded polarographically with a Clark-type electrode, while other measures were determined with standard fluorometric enzymatic methods. Results: Progressive impairment of liver mitochondrial respiration in the initial stage of ammonia-induced hepatotoxicity and the subsequent energy crisis due to decreased ATP synthesis lead to cessation of gluconeogenesis and ketogenesis. Reduction in glucose and ketone body supply to the brain is a terminal event in liver toxicity, preceding the development of coma. Conclusions: Our study provides a framework to further explore the relationship between hepatic dysfunction and progression of brain energy crisis in hepatic encephalopathy.<\/jats:p>","DOI":"10.3390\/jcm9072259","type":"journal-article","created":{"date-parts":[[2020,7,22]],"date-time":"2020-07-22T03:23:16Z","timestamp":1595388196000},"page":"2259","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A Look into Liver Mitochondrial Dysfunction as a Hallmark in Progression of Brain Energy Crisis and Development of Neurologic Symptoms in Hepatic Encephalopathy"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3293-652X","authenticated-orcid":false,"given":"Elena","family":"Kosenko","sequence":"first","affiliation":[{"name":"Institute of Theoretical and Experimental Biophysics of Russian Academy of Sciences, 142290 Pushchino, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6310-0242","authenticated-orcid":false,"given":"Lyudmila","family":"Tikhonova","sequence":"additional","affiliation":[{"name":"Institute of Theoretical and Experimental Biophysics of Russian Academy of Sciences, 142290 Pushchino, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gubidat","family":"Alilova","sequence":"additional","affiliation":[{"name":"Institute of Theoretical and Experimental Biophysics of Russian Academy of Sciences, 142290 Pushchino, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4740-4788","authenticated-orcid":false,"given":"Carmina","family":"Montoliu","sequence":"additional","affiliation":[{"name":"Hospital Clinico Research Foundation, INCLIVA Health Research Institute, 46010 Valencia, Spain"},{"name":"Pathology Department, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,16]]},"reference":[{"key":"ref_1","unstructured":"Von Frerichs, F.T. (1860). A Clinical Treatise on Diseases of the Liver by Dr Friedrich Theodor Frerichs, The New Sydenham Society."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/BF01995065","article-title":"Die Eck\u2019sche fistel zwischen der unteren hohlvene und der pfortader und ihre folgen fur den organismus","volume":"32","author":"Hahn","year":"1893","journal-title":"Arch. Exp. Pathol. Pharmakol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF02833598","article-title":"Ammonia: Key factor in the pathogenesis of hepatic encephalopathy","volume":"6","author":"Butterworth","year":"1987","journal-title":"Neurochem. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1053\/jhep.2000.17687","article-title":"The systemic inflammatory response syndrome in acute liver failure","volume":"32","author":"Rolando","year":"2000","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1177\/0148607187011006569","article-title":"Interorgan ammonia metabolism in health and disease: A surgeon\u2019s view","volume":"11","author":"Souba","year":"1987","journal-title":"J. Parenter. Enter. Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1093\/ajcn\/23.5.619","article-title":"Pathogenesis of hepatic encephalopathy--with special reference to the role of ammonia","volume":"23","author":"Walker","year":"1970","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_7","first-page":"105","article-title":"Hepatic encephalopathy: Experimental approaches to human metabolic encephalopathy","volume":"3","author":"Lockwood","year":"1987","journal-title":"Crit. Rev. Neurobiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1152\/physrev.1987.67.2.440","article-title":"Biochemistry and physiology of brain ammonia","volume":"67","author":"Cooper","year":"1987","journal-title":"Physiol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/BF02676355","article-title":"Effects of acute hyperammonemia in vivo on oxidative metabolism in nonsynaptic rat brain mitochondria","volume":"12","author":"Kosenko","year":"1997","journal-title":"Metab. Brain Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/S0006-8993(00)02785-2","article-title":"Alteration of mitochondrial calcium homeostasis by ammonia-induced activation of NMDA receptors in rat brain in vivo","volume":"880","author":"Kosenko","year":"2000","journal-title":"Brain Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1002\/(SICI)1098-1136(199709)21:1<124::AID-GLIA14>3.0.CO;2-U","article-title":"The glial glutamate transporter in hyperammonemia and hepatic encephalopathy: Relation to energy metabolism and glutamatergic neurotransmission","volume":"21","author":"Norenberg","year":"1997","journal-title":"Glia"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.1046\/j.1471-4159.1994.63062172.x","article-title":"Brain ATP depletion induced by acute ammonia intoxication in rats is mediated by activation of the NMDA receptor and Na+,K(+)-ATPase","volume":"63","author":"Kosenko","year":"1994","journal-title":"J. Neurochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"637","DOI":"10.3109\/10715769709097867","article-title":"Superoxide production and antioxidant enzymes in ammonia intoxication in rats","volume":"27","author":"Kosenko","year":"1997","journal-title":"Free Radic. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1053\/jhep.2003.50087","article-title":"Oxidative and nitrosative stress in ammonia neurotoxicity","volume":"37","author":"Norenberg","year":"2003","journal-title":"Hepatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1016\/j.jceh.2014.06.004","article-title":"Pathogenesis of hepatic encephalopathy: Role of ammonia and systemic inflammation","volume":"5","author":"Aldridge","year":"2015","journal-title":"J. Clin. Exp. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.jceh.2018.06.002","article-title":"Cerebral blood flow and metabolism in hepatic encephalopathy\u2014A meta-analysis","volume":"8","author":"Bjerring","year":"2018","journal-title":"J. Clin. Exp. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S1056-8719(99)00043-X","article-title":"An investigation of the relationship between the liver and brain using an isolated perfused rat brain preparation","volume":"42","author":"Alexander","year":"1999","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1007\/s10545-012-9553-3","article-title":"Effects of hypoglycaemia on neuronal metabolism in the adult brain: Role of alternative substrates to glucose","volume":"36","author":"Amaral","year":"2013","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1002\/cphy.c130024","article-title":"Energy metabolism in the liver","volume":"4","author":"Rui","year":"2014","journal-title":"Compr. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"472","DOI":"10.3109\/00365529209000107","article-title":"Evaluation of ketogenesis in seriously reduced hepatic mitochondrial redox state. An analysis of survivors and non-survivors in critically ill hepatectomized patients","volume":"27","author":"Yamaguchi","year":"1992","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1172\/JCI106016","article-title":"Liver and kidney metabolism during prolonged starvation","volume":"48","author":"Owen","year":"1969","journal-title":"J. Clin. Invest."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/S0899-9007(98)00191-9","article-title":"Nutritional support in hepatic encephalopathy","volume":"15","author":"Mizock","year":"1999","journal-title":"Nutrition"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1111\/j.1365-2362.1979.tb00903.x","article-title":"Lactate elimination in man: Effects of lactate concentration and hepatic dysfunction","volume":"9","author":"Woll","year":"1979","journal-title":"Eur. J. Clin. Invest."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1172\/JCI110240","article-title":"Hepatic, gut, and renal substrate flux rates in patients with hepatic cirrhosis","volume":"68","author":"Owen","year":"1981","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/0006-8993(79)90601-2","article-title":"Brain metabolism and specific transport at the blood-brain barrier after portocaval anastomosis in the rat","volume":"160","author":"Sarna","year":"1979","journal-title":"Brain Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1111\/j.1471-4159.1984.tb12789.x","article-title":"Portacaval anastomosis: Brain and plasma metabolite abnormalities and the effect of nutritional therapy","volume":"43","author":"Mans","year":"1984","journal-title":"J. Neurochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/0014-5793(89)80636-2","article-title":"Hyperammonemia decreases body fat content in rat","volume":"249","author":"Felipo","year":"1989","journal-title":"FEBS Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/0003-9861(91)90570-9","article-title":"Ammonium ingestion prevents depletion of hepatic energy metabolites induced by acute ammonium intoxication","volume":"290","author":"Kosenko","year":"1991","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"283","DOI":"10.7326\/0003-4819-132-4-200002150-00006","article-title":"Fatal hyperammonemia after orthotopic lung transplantation","volume":"132","author":"Lichtenstein","year":"2000","journal-title":"Ann. Intern. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1007\/s10024-001-0271-3","article-title":"Idiopathic hyperammonemia following an unrelated cord blood transplant for mucopolysaccharidosis I","volume":"6","author":"Snyder","year":"2003","journal-title":"Pediatr. Dev. Pathol. Off. J. Soc. Pediatr. Pathol. Paediatr. Pathol. Soc."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/0026-0495(71)90056-4","article-title":"Energy cost of gluconeogenesis in rat liver","volume":"20","author":"Williamson","year":"1971","journal-title":"Metabolism"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1111\/j.1471-4159.2004.02426.x","article-title":"Acute ammonia intoxication induces an NMDA receptor-mediated increase in poly(ADP-ribose) polymerase level and NAD metabolism in nuclei of rat brain cells","volume":"89","author":"Kosenko","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1139\/O08-134","article-title":"Encapsulation of glutamine synthetase in mouse erythrocytes: A new procedure for ammonia detoxification","volume":"86","author":"Kosenko","year":"2008","journal-title":"Biochem. Cell Biol. Biochim. Biol. Cell."},{"key":"ref_34","unstructured":"Graham, J.M. (2001). Purification of a crude mitochondrial fraction by density-gradient centrifugation. Curr. Protoc. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0021-9258(19)52451-6","article-title":"Protein measurement with the folin phenol reagent","volume":"193","author":"Lowry","year":"1951","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/S1385-299X(01)00071-X","article-title":"Preparation and handling of brain mitochondria useful to study uptake and release of calcium","volume":"7","author":"Kosenko","year":"2001","journal-title":"Brain Res. Brain Res. Protoc."},{"key":"ref_37","first-page":"1","article-title":"The identification of subcellular fractions from mammalian cells","volume":"19","author":"Graham","year":"1993","journal-title":"Methods Mol. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Graham, J.M. (2001). Isolation of mitochondria from tissues and cells by differential centrifugation. Curr. Protoc. Cell Biol.","DOI":"10.1002\/0471143030.cb0306s07"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/0076-6879(69)13043-8","article-title":"Pyruvate Carboxylase from Chicken Liver","volume":"Volume 13","author":"Lowenstein","year":"1969","journal-title":"Methods in Enzymology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/0003-2697(79)90582-7","article-title":"Determination of phosphoenolpyruvate carboxykinase activity with deoxyguanosine 5\u2032-diphosphate as nucleotide substrate","volume":"96","author":"Petrescu","year":"1979","journal-title":"Anal. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/0076-6879(89)74010-6","article-title":"Measurement of intactness of rat liver endoplasmic reticulum","volume":"174","author":"Arion","year":"1989","journal-title":"Methods Enzymol."},{"key":"ref_42","first-page":"876","article-title":"Glucose 6-phosphatase","volume":"Volume 2","author":"Bergmeyer","year":"1974","journal-title":"Methods of Enzymatic Analysis"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1042\/bj1080353","article-title":"Activity and intracellular distribution of enzymes of ketone-body metabolism in rat liver","volume":"108","author":"Williamson","year":"1968","journal-title":"Biochem. J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1042\/bj2620159","article-title":"Treatment of rats with glucagon or mannoheptulose increases mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase activity and decreases succinyl-CoA content in liver","volume":"262","author":"Quant","year":"1989","journal-title":"Biochem. J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5768","DOI":"10.1016\/S0021-9258(19)41120-4","article-title":"3-Hydroxy-3-methylglutaryl coenzyme A synthase. Evidence for an acetyl-S-enzyme intermediate and identification of a cysteinyl sulfhydryl as the site of acetylation","volume":"250","author":"Miziorko","year":"1975","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3108","DOI":"10.1016\/S0021-9258(19)41601-3","article-title":"Intracellular localization of the 3-hydroxy-3-methylglutaryl coenzme A cycle enzymes in liver. Separate cytoplasmic and mitochondrial 3-hydroxy-3-methylglutaryl coenzyme A generating systems for cholesterogenesis and ketogenesis","volume":"250","author":"Clinkenbeard","year":"1975","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/0009-8981(90)90314-I","article-title":"Rapid diagnosis of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency via enzyme activity measurements in leukocytes or platelets using a simple spectrophotometric method","volume":"189","author":"Wanders","year":"1990","journal-title":"Clin. Chim. Acta Int. J. Clin. Chem."},{"key":"ref_48","first-page":"1836","article-title":"Determination of Ketone Bodies","volume":"Volume 4","author":"Bergmeyer","year":"1974","journal-title":"Methods of Enzymatic Analysis"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1023\/A:1020626928259","article-title":"Nitroarginine, an inhibitor of nitric oxide synthase, prevents changes in superoxide radical and antioxidant enzymes induced by ammonia intoxication","volume":"13","author":"Kosenko","year":"1998","journal-title":"Metab. Brain Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/0742-8413(88)90101-6","article-title":"Diurnal changes in succinate and D-3-hydroxybutyrate dehydrogenase activities of rat liver mitochondria after chronic alcohol consumption and withdrawal","volume":"90","author":"Kaminsky","year":"1988","journal-title":"Comp. Biochem. Physiol. C"},{"key":"ref_51","first-page":"E498","article-title":"Altered hepatic mitochondrial fatty acid oxidation and ketogenesis in endotoxic rats","volume":"259","author":"Takeyama","year":"1990","journal-title":"Am. J. Physiol."},{"key":"ref_52","unstructured":"Kosenko, E.A., Venediktova, N.I., and Kaminski\u012d, I.G. (2003). Calcium and ammonia stimulate monoamine oxidase A activity in brain mitochondria. Izv. Akad. Nauk. Ser. Biol., 542\u2013546."},{"key":"ref_53","first-page":"196","article-title":"Calculation of the concentration of metabolites freely and non-freely penetrating the cell membranes in the liver cylosol and mitochondria","volume":"2","author":"Kaminsky","year":"1987","journal-title":"Izv SSRR Ser. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1111\/j.1432-1033.1970.tb00880.x","article-title":"Regulation of pyruvate carboxylase in rat liver mitochondria by adenine nucleotides and short chain fatty acids","volume":"12","author":"Walter","year":"1970","journal-title":"Eur. J. Biochem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1042\/bj1030514","article-title":"The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver","volume":"103","author":"Williamson","year":"1967","journal-title":"Biochem. J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1152\/ajplegacy.1969.217.5.1269","article-title":"Depletion of reduced pyridine nucleotides in liver and blood with ammonia","volume":"217","author":"Clifford","year":"1969","journal-title":"Am. J. Physiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1042\/bj1480353b","article-title":"The effects of inhibition of gluconeogenesis on ketogenesis in starved and diabetic rats","volume":"148","author":"Blackshear","year":"1975","journal-title":"Biochem. J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S0006-8993(03)03035-X","article-title":"Sources of oxygen radicals in brain in acute ammonia intoxication in vivo","volume":"981","author":"Kosenko","year":"2003","journal-title":"Brain Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1056\/NEJM198507253130405","article-title":"Glucose counterregulation, hypoglycemia, and intensive insulin therapy in diabetes mellitus","volume":"313","author":"Cryer","year":"1985","journal-title":"N. Engl. J. Med."},{"key":"ref_60","unstructured":"Kosenko, E.A. (2014). Energy Metabolism in Normal and in Pathology. The Role of Stimulating Neurotransmitter, Lenand."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0006-3002(62)90146-4","article-title":"Mechanism of inhibitory action of ammonia on the respiration of rat-liver mitochondria","volume":"65","author":"Worcel","year":"1962","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1007\/BF00765158","article-title":"Effect of long-chain fatty acids and acyl-CoA on mitochondrial permeability, transport, and energy-coupling processes","volume":"8","author":"Wojtczak","year":"1976","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0304-3940(97)13476-0","article-title":"Progressive decrease of cerebral cytochrome C oxidase activity in sparse-fur mice: Role of acetyl-L-carnitine in restoring the ammonia-induced cerebral energy depletion","volume":"224","author":"Rao","year":"1997","journal-title":"Neurosci. Lett."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.1002\/jnr.21385","article-title":"Acute ammonia neurotoxicity in vivo involves increase in cytoplasmic protein P53 without alterations in other markers of apoptosis","volume":"85","author":"Kosenko","year":"2007","journal-title":"J. Neurosci. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.2337\/db12-1311","article-title":"Targeting pyruvate carboxylase reduces gluconeogenesis and adiposity and improves insulin resistance","volume":"62","author":"Kumashiro","year":"2013","journal-title":"Diabetes"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/7\/2259\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:49:02Z","timestamp":1760176142000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/7\/2259"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,16]]},"references-count":65,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,7]]}},"alternative-id":["jcm9072259"],"URL":"https:\/\/doi.org\/10.3390\/jcm9072259","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,16]]}}}