{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T21:24:50Z","timestamp":1793741090241,"version":"4.6.1"},"reference-count":191,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T00:00:00Z","timestamp":1744588800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["CA275840"],"award-info":[{"award-number":["CA275840"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Ketogenesis, a mitochondrial metabolic pathway, occurs primarily in liver, but kidney, colon and retina are also capable of this pathway. It is activated during fasting and exercise, by \u201cketo\u201d diets, and in diabetes as well as during therapy with SGLT2 inhibitors. The principal ketone body is \u03b2-hydroxybutyrate, a widely recognized alternative energy source for extrahepatic tissues (brain, heart, muscle, and kidney) when blood glucose is sparse or when glucose transport\/metabolism is impaired. Recent studies have identified new functions for \u03b2-hydroxybutyrate: it serves as an agonist for the G-protein-coupled receptor GPR109A and also works as an epigenetic modifier. Ketone bodies protect against inflammation, cancer, and neurodegeneration. HMGCS2, as the rate-limiting enzyme, controls ketogenesis. Its expression and activity are regulated by transcriptional and post-translational mechanisms with glucagon, insulin, and glucocorticoids as the principal participants. Loss-of-function mutations occur in HMGCS2 in humans, resulting in a severe metabolic disease. These patients typically present within a year after birth with metabolic acidosis, hypoketotic hypoglycemia, hepatomegaly, steatotic liver damage, hyperammonemia, and neurological complications. Nothing is known about the long-term consequences of this disease. This review provides an up-to-date summary of the biological functions of ketone bodies with a special focus on HMGCS2 in health and disease.<\/jats:p>","DOI":"10.3390\/biom15040580","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T08:11:39Z","timestamp":1744704699000},"page":"580","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Not Just an Alternative Energy Source: Diverse Biological Functions of Ketone Bodies and Relevance of HMGCS2 to Health and Disease"],"prefix":"10.3390","volume":"15","author":[{"given":"Varshini V.","family":"Suresh","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9230-0144","authenticated-orcid":false,"given":"Sathish","family":"Sivaprakasam","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangzom D.","family":"Bhutia","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puttur D.","family":"Prasad","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muthusamy","family":"Thangaraju","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vadivel","family":"Ganapathy","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1152\/physrev.1980.60.1.143","article-title":"Physiological roles of ketone bodies as substrates and signals in mammalian tissues","volume":"60","author":"Robinson","year":"1980","journal-title":"Physiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1146\/annurev.bi.49.070180.002143","article-title":"Regulation of Hepatic Fatty Acid Oxidation and Ketone Body Production","volume":"49","author":"McGarry","year":"1980","journal-title":"Annu. Rev. Biochem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev.nutr.26.061505.111258","article-title":"Fuel Metabolism in Starvation","volume":"26","author":"Cahill","year":"2006","journal-title":"Annu. Rev. Nutr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1113\/jphysiol.1980.sp013190","article-title":"Post-exercise ketosis","volume":"301","author":"Koeslag","year":"1980","journal-title":"J. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Torrens, S.L., Robergs, R.A., Curry, S.C., and Nalos, M. (2023). The Computational Acid\u2013Base Chemistry of Hepatic Ketoacidosis. Metabolites, 13.","DOI":"10.3390\/metabo13070803"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"116592","DOI":"10.1016\/j.lfs.2019.116592","article-title":"The recent insights into the function of ACAT1: A possible anti-cancer therapeutic target","volume":"232","author":"Goudarzi","year":"2019","journal-title":"Life Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1146\/annurev-nutr-071816-064916","article-title":"\u03b2-Hydroxybutyrate: A signaling metabolite","volume":"37","author":"Newman","year":"2017","journal-title":"Annu. Rev. Nutr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/S0955-2863(97)00048-X","article-title":"Nutritional role of the leucine metabolite \u03b2-hydroxy \u03b2-methylbutyrate (HMB)","volume":"8","author":"Nissen","year":"1997","journal-title":"Nutr. Biochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1007\/s10545-016-9933-1","article-title":"On the origin of 3-methylglutaconic acid in disorders of mitochondrial energy metabolism","volume":"39","author":"Ikon","year":"2016","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1002\/humu.23831","article-title":"Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency","volume":"40","author":"Abdelkreem","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/ped.12585","article-title":"Inborn errors of ketone body utilization","volume":"57","author":"Hori","year":"2015","journal-title":"Pediatr. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1007\/s10545-013-9589-z","article-title":"A structural mapping of mutations causing succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency","volume":"36","author":"Shafqat","year":"2013","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_13","first-page":"45","article-title":"Metabolic effects of glucagon in humans","volume":"15","year":"2018","journal-title":"J. Clin. Transl. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1023\/A:1006827227162","article-title":"Protein phosphatase-1 and insulin action","volume":"182","author":"Ragolia","year":"1998","journal-title":"Mol. Cell. Biochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1111\/cen.12095","article-title":"Fibroblast Growth Factor 21 as an emerging metabolic regulator: Clinical perspectives","volume":"78","author":"Woo","year":"2012","journal-title":"Clin. Endocrinol."},{"key":"ref_16","first-page":"88","article-title":"Fibroblast growth factor 21: Update on genetics and molecular biology","volume":"36","author":"Barros","year":"2024","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1042\/bj1120149","article-title":"The fuel of respiration of rat kidney cortex","volume":"112","author":"Weidemann","year":"1969","journal-title":"Biochem. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"18944","DOI":"10.1038\/srep18944","article-title":"Mammalian autophagy is essential for hepatic and renal ketogenesis during starvation","volume":"6","author":"Takagi","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"F460","DOI":"10.1152\/ajprenal.00447.2021","article-title":"Fasting-induced HMGCS2 expression in the kidney does not contribute to circulating ketones","volume":"322","author":"Venable","year":"2022","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_20","first-page":"E287","article-title":"Proteomics analysis reveals diabetic kidney as a ketogenic organ in type 2 diabetes","volume":"300","author":"Zhang","year":"2011","journal-title":"Am. J. Physiol. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/S0039-6060(96)80193-0","article-title":"Enhanced ketogenesis in the kidney during hepatic inflow occlusion with the administration of Ringer\u2019s acetate solution","volume":"119","author":"Nakatani","year":"1996","journal-title":"Surgery"},{"key":"ref_22","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. Investig."},{"key":"ref_23","unstructured":"(2025, February 27). Available online: https:\/\/v24.proteinatlas.org\/ENSG00000134240-HMGCS2\/tissue."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.cmet.2016.12.022","article-title":"Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics","volume":"25","author":"Puchalska","year":"2017","journal-title":"Cell Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1136\/gutjnl-2019-319372","article-title":"Suppression of enteroendocrine cell glucagon-like peptide (GLP)-1 release by fat-induced small intestinal ketogenesis: A mechanism targeted by Roux-en-Y gastric bypass surgery but not by preoperative very-low-calorie diet","volume":"69","author":"Wallenius","year":"2019","journal-title":"Gut"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.freeradbiomed.2021.05.032","article-title":"Ketogenesis alleviates TNF\u03b1-induced apoptosis and inflammatory responses in intestinal cells","volume":"172","author":"Kim","year":"2021","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2298","DOI":"10.1091\/mbc.E14-02-0736","article-title":"Keratin 8 absence down-regulates colonocyte HMGCS2 and modulates colonic ketogenesis and energy metabolism","volume":"26","author":"Helenius","year":"2015","journal-title":"Mol. Biol. Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1042\/BCJ20230403","article-title":"Colonic ketogenesis, a microbiota-regulated process, contributes to blood ketones and protects against colitis in mice","volume":"481","author":"Bass","year":"2024","journal-title":"Biochem. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"107565","DOI":"10.1016\/j.celrep.2020.107565","article-title":"Region-Specific Proteome Changes of the Intestinal Epithelium during Aging and Dietary Restriction","volume":"31","author":"Gebert","year":"2020","journal-title":"Cell Rep."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Kim, J.T., Li, C., Weiss, H.L., Zhou, Y., Liu, C., Wang, Q., and Evers, B.M. (2019). Regulation of Ketogenic Enzyme HMGCS2 by Wnt\/\u03b2-catenin\/PPAR\u03b3 Pathway in Intestinal Cells. Cells, 8.","DOI":"10.3390\/cells8091106"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1159\/000243256","article-title":"An Explanation for Ketogenesis by the Intestine of the Suckling Rat: The Presence of an Active Hydroxymethylglutaryl-Coenzyme A Pathway","volume":"58","author":"Williamson","year":"1990","journal-title":"Neonatology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1006\/abbi.1993.1169","article-title":"Ketogenic Mitochondrial 3-Hydroxy 3-Methylglutaryl-CoA Synthase Gene Expression in Intestine and Liver of Suckling Rats","volume":"301","author":"Serra","year":"1993","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1111\/j.1432-1033.1996.0016n.x","article-title":"The expression of mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme-A synthase in neonatal rat intestine and liver is under transcriptional control","volume":"237","author":"Serra","year":"1996","journal-title":"Eur. J. Biochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/j.cell.2019.07.048","article-title":"Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet","volume":"178","author":"Cheng","year":"2019","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"110044","DOI":"10.1016\/j.celrep.2021.110044","article-title":"Reprogramming of H3K9bhb at regulatory elements is a key feature of fasting in the small intestine","volume":"37","author":"Terranova","year":"2021","journal-title":"Cell Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/cdd.2016.142","article-title":"Ketogenesis contributes to intestinal cell differentiation","volume":"24","author":"Wang","year":"2017","journal-title":"Cell Death Differ."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"20570","DOI":"10.1074\/jbc.M114.565457","article-title":"The Retinal Pigment Epithelium Utilizes Fatty Acids for Ketogenesis","volume":"289","author":"Adijanto","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3468","DOI":"10.1167\/iovs.19-26690","article-title":"Highly Differentiated Human Fetal RPE Cultures Are Resistant to the Accumulation and Toxicity of Lipofuscin-Like Material","volume":"60","author":"Zhang","year":"2019","journal-title":"Investig. Opthalmology Vis. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"109966","DOI":"10.1016\/j.exer.2024.109966","article-title":"Reassessing retinal pigment epithelial ketogenesis: Enzymatic assays for ketone body levels provide inaccurate results","volume":"245","author":"Gulette","year":"2024","journal-title":"Exp. Eye Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8038","DOI":"10.1074\/jbc.M116.770784","article-title":"Phagocytosis-dependent ketogenesis in retinal pigment epithelium","volume":"292","author":"Dhingra","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.plefa.2003.05.001","article-title":"Ketone body synthesis in the brain: Possible neuroprotective effects","volume":"70","year":"2004","journal-title":"Prostaglandins Leukot. Essent. Fat. Acids"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1111\/j.1471-4159.1991.tb11435.x","article-title":"Fatty Acid Oxidation and Ketogenesis by Astrocytes in Primary Culture","volume":"56","author":"Auestad","year":"1991","journal-title":"J. Neurochem."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Takahashi, S., Iizumi, T., Mashima, K., Abe, T., and Suzuki, N. (2014). Roles and Regulation of Ketogenesis in Cultured Astroglia and Neurons Under Hypoxia and Hypoglycemia. ASN Neuro, 6.","DOI":"10.1177\/1759091414550997"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1046\/j.1471-4159.1999.731674.x","article-title":"The AMP-Activated Protein Kinase Is Involved in the Regulation of Ketone Body Production by Astrocytes","volume":"73","author":"Woods","year":"1999","journal-title":"J. Neurochem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/s42255-022-00528-6","article-title":"Glia fuel neurons with locally synthesized ketone bodies to sustain memory under starvation","volume":"4","author":"Silva","year":"2022","journal-title":"Nat. Metab."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2996","DOI":"10.1038\/s41467-023-38813-x","article-title":"Glycolytically impaired Drosophila glial cells fuel neural metabolism via \u03b2-oxidation","volume":"14","author":"McMullen","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2518","DOI":"10.1007\/s12035-016-9833-2","article-title":"Metabolic and Inflammatory Adaptation of Reactive Astrocytes: Role of PPARs","volume":"54","author":"Iglesias","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"C761","DOI":"10.1152\/ajpcell.1993.264.4.C761","article-title":"Transport of lactate and other monocarboxylates across mammalian plasma membranes","volume":"264","author":"Poole","year":"1993","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1208\/s12248-008-9022-y","article-title":"Sodium-coupled Monocarboxylate Transporters in Normal Tissues and in Cancer","volume":"10","author":"Ganapathy","year":"2008","journal-title":"AAPS J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/j.2040-4603.2018.tb00009.x","article-title":"Short-Chain Fatty Acid Transporters: Role in Colonic Homeostasis","volume":"8","author":"Sivaprakasam","year":"2017","journal-title":"Compr. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1124\/pr.119.018762","article-title":"Monocarboxylate Transporters (SLC16): Function, Regulation, and Role in Health and Disease","volume":"72","author":"Felmlee","year":"2020","journal-title":"Pharmacol. Rev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"13293","DOI":"10.1074\/jbc.C400059200","article-title":"Functional Identification of SLC5A8, a Tumor Suppressor Down-regulated in Colon Cancer, as a Na+-coupled Transporter for Short-chain Fatty Acids","volume":"279","author":"Miyauchi","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"44522","DOI":"10.1074\/jbc.M405365200","article-title":"Expression of slc5a8 in Kidney and Its Role in Na+-coupled Transport of Lactate","volume":"279","author":"Gopal","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1042\/BJ20041916","article-title":"Sodium-coupled and electrogenic transport of B-complex vitamin nicotinic acid by slc5a8, a member of the Na\/glucose co-transporter gene family","volume":"388","author":"Gopal","year":"2005","journal-title":"Biochem. J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1111\/j.1471-4159.2006.03878.x","article-title":"Identity of SMCT1 (SLC5A8) as a neuron-specific Na+-coupled transporter for active uptake of L-lactate and ketone bodies in the brain","volume":"98","author":"Martin","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1471-4159.2005.03168.x","article-title":"Monocarboxylate transporters in the central nervous system: Distribution, regulation and function","volume":"94","author":"Pierre","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1023\/A:1013310210710","article-title":"MCT1-Mediated Transport of L-Lactic Acid at the Inner Blood\u2013Retinal Barrier: A Possible Route for Delivery of Monocarboxylic Acid Drugs to the Retina","volume":"18","author":"Hosoya","year":"2001","journal-title":"Pharm. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3956","DOI":"10.4161\/cc.22136","article-title":"Ketone bodies and two-compartment tumor metabolism: Stromal ketone production fuels mitochondrial biogenesis in epithelial cancer cells","volume":"11","author":"Lin","year":"2012","journal-title":"Cell Cycle"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1167\/iovs.02-0287","article-title":"Polarized Expression of Monocarboxylate Transporters in Human Retinal Pigment Epithelium and ARPE-19 Cells","volume":"44","author":"Philp","year":"2003","journal-title":"Investig. Opthalmology Vis. Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1097\/00004647-200205000-00010","article-title":"MCT2 is a Major Neuronal Monocarboxylate Transporter in the Adult Mouse Brain","volume":"22","author":"Pierre","year":"2002","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1101\/gad.180968.111","article-title":"A monocarboxylate transporter required for hepatocyte secretion of ketone bodies during fasting","volume":"26","author":"Hugo","year":"2012","journal-title":"Genes Dev."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Uebanso, T., Fukui, M., Naito, C., Shimohata, T., Mawatari, K., and Takahashi, A. (2023). SLC16a6, mTORC1, and Autophagy Regulate Ketone Body Excretion in the Intestinal Cells. Biology, 12.","DOI":"10.3390\/biology12121467"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Higuchi, K., Sugiyama, K., Tomabechi, R., Kishimoto, H., and Inoue, K. (2022). Mammalian monocarboxylate transporter 7 (MCT7\/Slc16a6) is a novel facilitative taurine transporter. J. Biol. Chem., 298.","DOI":"10.1016\/j.jbc.2022.101800"},{"key":"ref_64","unstructured":"(2025, February 27). Available online: https:\/\/www.proteinatlas.org\/ENSG00000108932-SLC16A6\/tissue."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1161\/CIRCRESAHA.123.321872","article-title":"Ketones and the Heart: Metabolic Principles and Therapeutic Implications","volume":"132","author":"Matsuura","year":"2023","journal-title":"Circ. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"919","DOI":"10.2174\/0113894501312168240821082224","article-title":"Beta-Hydroxybutyrate: A Supplemental Molecule for Various Diseases","volume":"25","author":"Shahtaghi","year":"2024","journal-title":"Curr. Drug Targets"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Jang, J., Kim, S.R., Lee, J.E., Lee, S., Son, H.J., Choe, W., Yoon, K.-S., Kim, S.S., Yeo, E.-J., and Kang, I. (2023). Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25010124"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12916-021-02185-0","article-title":"Ketone bodies: From enemy to friend and guardian angel","volume":"19","author":"Kolb","year":"2021","journal-title":"BMC Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1152\/physiol.00031.2023","article-title":"Emerging Pathophysiological Roles of Ketone Bodies","volume":"39","author":"Tsuruta","year":"2024","journal-title":"Physiology"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"pgac142","DOI":"10.1093\/pnasnexus\/pgac142","article-title":"Frataxin controls ketone body metabolism through regulation of OXCT1","volume":"1","author":"Mesaros","year":"2022","journal-title":"PNAS Nexus"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.molcel.2023.11.042","article-title":"OXCT1 functions as a succinyltransferase, contributing to hepatocellular carcinoma via succinylating LACTB","volume":"84","author":"Ma","year":"2024","journal-title":"Mol. Cell"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/j.molcel.2024.12.025","article-title":"OXCT1 succinylation and activation by SUCLA2 promotes ketolysis and liver tumor growth","volume":"85","author":"Guo","year":"2025","journal-title":"Mol. Cell"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Spigoni, V., Cinquegrani, G., Iannozzi, N.T., Frigeri, G., Maggiolo, G., Maggi, M., Parello, V., and Cas, A.D. (2022). Activation of G protein-coupled receptors by ketone bodies: Clinical implication of the ketogenic diet in metabolic disorders. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.972890"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.tem.2016.11.007","article-title":"Hydroxy-Carboxylic Acid Receptor Actions in Metabolism","volume":"28","author":"Offermanns","year":"2017","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.coph.2013.08.006","article-title":"Transporters and receptors for short-chain fatty acids as the molecular link between colonic bacteria and the host","volume":"13","author":"Ganapathy","year":"2013","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"26649","DOI":"10.1074\/jbc.C500213200","article-title":"(d)-\u03b2-Hydroxybutyrate Inhibits Adipocyte Lipolysis via the Nicotinic Acid Receptor PUMA-G","volume":"280","author":"Taggart","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2826","DOI":"10.1158\/0008-5472.CAN-08-4466","article-title":"GPR109A Is a G-protein\u2013Coupled Receptor for the Bacterial Fermentation Product Butyrate and Functions as a Tumor Suppressor in Colon","volume":"69","author":"Thangaraju","year":"2009","journal-title":"Cancer Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"19314","DOI":"10.1523\/JNEUROSCI.3102-13.2013","article-title":"\u03b2-Hydroxybutyrate modulates N-type calcium channels in rat sympathetic neurons by acting as an agonist for the G-protein-coupled receptor FFA3","volume":"33","author":"Won","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"8030","DOI":"10.1073\/pnas.1016088108","article-title":"Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41)","volume":"108","author":"Kimura","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"23813","DOI":"10.1073\/pnas.1912573116","article-title":"Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions","volume":"116","author":"Miyamoto","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1093\/jleuko\/qiad035","article-title":"The ketone body acetoacetate activates human neutrophils through FFAR2","volume":"113","author":"Lind","year":"2023","journal-title":"J. Leukoc. Biol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1074\/jbc.M115.676510","article-title":"Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice","volume":"291","author":"Zou","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Wu, X.-J., Shu, Q.-Q., Wang, B., Dong, L., and Hao, B. (2022). Acetoacetate Improves Memory in Alzheimer\u2019s Mice via Promoting Brain-Derived Neurotrophic Factor and Inhibiting Inflammation. Am. J. Alzheimer\u2019s Dis. Other Dementiasr, 37.","DOI":"10.1177\/15333175221124949"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.1038\/s42255-023-00935-3","article-title":"Metabolic Messengers: Ketone bodies","volume":"5","author":"Nelson","year":"2023","journal-title":"Nat. Metab."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Andersen, O.E., Poulsen, J.V., Farup, J., and de Morree, A. (2023). Regulation of adult stem cell function by ketone bodies. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1246998"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"dgaa370","DOI":"10.1210\/clinem\/dgaa370","article-title":"Ketone body, 3-hydroxybutyrate: Minor metabolite\u2014major medical manifestations","volume":"105","author":"Moller","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1126\/science.1227166","article-title":"Suppression of oxidative stress by \u03b2-hydroxybutyrate, an endogenous histone deacetylase inhibitor","volume":"339","author":"Shimazu","year":"2013","journal-title":"Science"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e15092","DOI":"10.7554\/eLife.15092","article-title":"Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body \u03b2-hydroxybutyrate","volume":"5","author":"Sleiman","year":"2016","journal-title":"eLife"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1111\/gtc.12456","article-title":"Epigenetic regulation of the glucose transporter gene Slc2a1 by \u03b2-hydroxybutyrate underlies preferential glucose supply to the brain of fasted mice","volume":"22","author":"Tanegashima","year":"2016","journal-title":"Genes Cells"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.cmet.2017.08.015","article-title":"Distinct Circadian Signatures in Liver and Gut Clocks Revealed by Ketogenic Diet","volume":"26","author":"Tognini","year":"2017","journal-title":"Cell Metab."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.neuroscience.2017.09.056","article-title":"Ketogenic Metabolism Inhibits Histone Deacetylase (HDAC) and Reduces Oxidative Stress After Spinal Cord Injury in Rats","volume":"366","author":"Wang","year":"2017","journal-title":"Neuroscience"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1007\/s00125-020-05305-2","article-title":"\u03b2-Hydroxybutyrate inhibits histone deacetylase 3 to promote claudin-5 generation and attenuate cardiac microvascular hyperpermeability in diabetes","volume":"64","author":"Li","year":"2020","journal-title":"Diabetologia"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Oka, S.-I., Tang, F., Chin, A., Ralda, G., Xu, X., Hu, C., Yang, Z., Abdellatif, M., and Sadoshima, J. (2021). \u03b2-Hydroxybutyrate, a Ketone Body, Potentiates the Antioxidant Defense via Thioredoxin 1 Upregulation in Cardiomyocytes. Antioxidants, 10.","DOI":"10.3390\/antiox10071153"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1038\/s41386-021-01212-1","article-title":"Rescue of histone hypoacetylation and social deficits by ketogenic diet in a Shank3 mouse model of autism","volume":"47","author":"Qin","year":"2021","journal-title":"Neuropsychopharmacology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1016\/j.cmet.2022.04.012","article-title":"Fasting induces a highly resilient deep quiescent state in muscle stem cells via ketone body signaling","volume":"34","author":"Benjamin","year":"2022","journal-title":"Cell Metab."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Chriett, S., Dabek, A., Wojtala, M., Vidal, H., Balcerczyk, A., and Pirola, L. (2019). Prominent action of butyrate over \u03b2-hydroxybutyrate as histone deacetylase inhibitor, transcriptional modulator and anti-inflammatory molecule. Sci. Rep., 9.","DOI":"10.1038\/s41598-018-36941-9"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Zhou, T., Cheng, X., He, Y., Xie, Y., Xu, F., Xu, Y., and Huang, W. (2022). Function and mechanism of histone \u03b2-hydroxybutyrylation in health and disease. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.981285"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e21098","DOI":"10.1016\/j.heliyon.2023.e21098","article-title":"\u03b2-Hydroxybutyrate as an epigenetic modifier: Underlying mechanisms and implications","volume":"9","author":"He","year":"2023","journal-title":"Heliyon"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.molcel.2016.03.036","article-title":"Metabolic Regulation of Gene Expression by Histone Lysine \u03b2-Hydroxybutyrylation","volume":"62","author":"Xie","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"eabe2771","DOI":"10.1126\/sciadv.abe2771","article-title":"The regulatory enzymes and protein substrates for the lysine \u03b2-hydroxybutyrylation pathway","volume":"7","author":"Huang","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"e2400426","DOI":"10.1002\/advs.202400426","article-title":"Adaptive Metabolic Responses Facilitate Blood-Brain Barrier Repair in Ischemic Stroke via BHB-Mediated Epigenetic Modification of ZO-1 Expression","volume":"11","author":"Li","year":"2024","journal-title":"Adv. Sci."},{"key":"ref_102","unstructured":"(2025, February 27). Available online: https:\/\/v24.proteinatlas.org\/ENSG00000112972-HMGCS1\/tissue."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue-Based Map of the Human Proteome","volume":"347","author":"Fagerberg","year":"2015","journal-title":"Science"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/S0022-2275(20)39673-5","article-title":"Testis and ovary express the gene for the ketogenic mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase","volume":"34","author":"Royo","year":"1993","journal-title":"J. Lipid Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/0303-7207(83)90056-4","article-title":"Mitochondrial biosynthesis of cholesterol in leydig cells from rat testis","volume":"33","author":"Pignataro","year":"1983","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/S0021-9258(19)68388-2","article-title":"Isolation and characterization of a mammalian cell mutant defective in 3-hydroxy-3-methylglutaryl coenzyme A synthase","volume":"257","author":"Logel","year":"1982","journal-title":"J. Biol. Chem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"10142","DOI":"10.1074\/jbc.M117.788778","article-title":"HMG-CoA synthase 1 is a synthetic lethal partner of BRAFV600E in human cancers","volume":"292","author":"Zhao","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"33227","DOI":"10.1074\/jbc.M112.393231","article-title":"Identification and Characterization of an Extramitochondrial Human 3-Hydroxy-3-methylglutaryl-CoA Lyase","volume":"287","author":"Montgomery","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Arnedo, M., Latorre-Pellicer, A., Lucia-Campos, C., Gil-Salvador, M., Anto\u00f1anzas-Per\u00e9z, R., G\u00f3mez-Puertas, P., Bueno-Lozano, G., Puisac, B., and Pi\u00e9, J. (2019). More Than One HMG-CoA Lyase: The Classical Mitochondrial Enzyme Plus the Peroxisomal and the Cytosolic Ones. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20246124"},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Wang, Y.-H., Suk, F.-M., and Liao, Y.-J. (2020). Loss of HMGCS2 Enhances Lipogenesis and Attenuates the Protective Effect of the Ketogenic Diet in Liver Cancer. Cancers, 12.","DOI":"10.3390\/cancers12071797"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"3874","DOI":"10.1073\/pnas.87.10.3874","article-title":"Rat mitochondrial and cytosolic 3-hydroxy-3-methylglutaryl-CoA synthases are encoded by two different genes","volume":"87","author":"Haro","year":"1990","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1006\/abbi.1995.1178","article-title":"Molecular cloning and tissue expression of human mitochnondrial 3-hydroxy-3-methylglutaryl-C0A synthase","volume":"317","author":"Mascaro","year":"1995","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/S0300-9084(00)88874-4","article-title":"Transcriptional regulation of mitochondrial HMG-CoA synthase in the control of ketogenesis","volume":"80","author":"Hegardt","year":"1998","journal-title":"Biochimie"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1042\/bj3380569","article-title":"Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: A control enzyme in ketogenesis","volume":"338","author":"Hegardt","year":"1999","journal-title":"Biochem. J."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0378-1119(97)00067-X","article-title":"Cloning and characterization of the human mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase gene","volume":"195","author":"Boukaftane","year":"1997","journal-title":"Gene"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"7488","DOI":"10.1073\/pnas.84.21.7488","article-title":"Inhibition of hydroxymethylglutaryl-coenzyme A synthase by L-659,699","volume":"84","author":"Greenspan","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1042\/bj2890889","article-title":"Inhibition of 3-hydroxy-3-methylglutaryl-CoA synthase and cholesterol biosynthesis by \u03b2-lactone inhibitors and binding of these inhibitors to the enzyme","volume":"289","author":"Greenspan","year":"1993","journal-title":"Biochem. J."},{"key":"ref_118","first-page":"22","article-title":"Binding site for fungal \u03b2-lactone hymeglusin on cytosolic 3-hydroxy-3-methylglutaryl coenzyme A synthase","volume":"1636","author":"Tomoda","year":"2004","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Cell Biol. Lipids"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1006\/bbrc.1999.1712","article-title":"Differential Inhibition of HMG-CoA Synthase and Pancreatic Lipase by the Specific Chiral Isomers of \u03b2-Lactone DU-6622","volume":"265","author":"Tomoda","year":"1999","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"475","DOI":"10.3233\/JAD-240376","article-title":"Computational Screening of Repurposed Drugs for HMG-CoA Synthase 2 in Alzheimer\u2019s Disease","volume":"100","author":"Shamsi","year":"2024","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Grabacka, M., Pierzchalska, M., Dean, M., and Reiss, K. (2016). Regulation of Ketone Body Metabolism and the Role of PPAR\u03b1. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17122093"},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Hwang, C.Y., Choe, W., Yoon, K.-S., Ha, J., Kim, S.S., Yeo, E.-J., and Kang, I. (2022). Molecular Mechanisms for Ketone Body Metabolism, Signaling Functions, and Therapeutic Potential in Cancer. Nutrients, 14.","DOI":"10.3390\/nu14224932"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.tem.2023.10.002","article-title":"Mechanisms of hepatic fatty acid oxidation and ketogenesis during fasting","volume":"35","author":"Ruppert","year":"2023","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_124","first-page":"246","article-title":"Cell-surface G-protein-coupled receptors for tumor-associated metabolites: A direct link to mitochondrial dysfunction in cancer","volume":"1868","author":"Ristic","year":"2017","journal-title":"Biochim. Biophys. Acta (BBA)-Bioenerg."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"254S","DOI":"10.3945\/ajcn.2009.28449B","article-title":"Fibroblast growth factor 21: From pharmacology to physiology","volume":"91","author":"Mangelsdorf","year":"2010","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Xie, J., and Weiskirchen, R. (2020). What does the \u201cAKT\u201d stand for in the name \u201cAKT kinase\u201d? Some historical comments. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.01329"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.cmet.2013.01.014","article-title":"Glucagon-Induced Acetylation of Foxa2 Regulates Hepatic Lipid Metabolism","volume":"17","author":"Porstmann","year":"2013","journal-title":"Cell Metab."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1093\/hmg\/ddt393","article-title":"Elevated FGF21, PGC-1\u03b1 and ketogenic enzyme expression are hallmarks of iron-sulfur cluster depletion in human skeletal muscle","volume":"23","author":"Crooks","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1289\/ehp.1103593","article-title":"Aryl Hydrocarbon Receptor Deficiency Enhances Insulin Sensitivity and Reduces PPAR-\u03b1 Pathway Activity in Mice","volume":"119","author":"Wang","year":"2011","journal-title":"Environ. Health Perspect."},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Sivaprakasam, S., Bhutia, Y.D., Ramachandran, S., and Ganapathy, V. (2017). Cell-Surface and Nuclear Receptors in the Colon as Targets for Bacterial Metabolites and Its Relevance to Colon Health. Nutrients, 9.","DOI":"10.3390\/nu9080856"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1097\/00004836-200603000-00015","article-title":"Colonic Health: Fermentation and Short Chain Fatty Acids","volume":"40","author":"Wong","year":"2006","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"6972","DOI":"10.1093\/emboj\/17.23.6972","article-title":"A mitochondrial ketogenic enzyme regulates its gene expression by association with the nuclear hormone receptor PPAR\u03b1","volume":"17","author":"Meertens","year":"1998","journal-title":"EMBO J."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1096\/fj.09-149765","article-title":"Palmitoylation of ketogenic enzyme HMGCS2 enhances its interaction with PPAR\u03b1 and transcription at the Hmgcs2 PPRE","volume":"24","author":"Kostiuk","year":"2010","journal-title":"FASEB J."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1038\/s41416-021-01490-y","article-title":"SLC38A4 functions as a tumour suppressor in hepatocellular carcinoma through modulating Wnt\/\u03b2-catenin\/MYC\/HMGCS2 axis","volume":"125","author":"Li","year":"2021","journal-title":"Br. J. Cancer"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/S0005-2736(00)00349-7","article-title":"Structure and function of ATA3, a new subtype of amino acid transport system A, primarily expressed in the liver and skeletal muscle","volume":"1509","author":"Sugawara","year":"2000","journal-title":"Biochim. Biophys. Acta (BBA)-Biomembr."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/S0005-2736(00)00390-4","article-title":"Evidence for the transport of neutral as well as cationic amino acids by ATA3, a novel and liver-specific subtype of amino acid transport system A","volume":"1510","author":"Hatanaka","year":"2001","journal-title":"Biochim. Biophys. Acta (BBA)-Biomembr."},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"Morace, C., Lorello, G., Bellone, F., Quartarone, C., Ruggeri, D., Giandalia, A., Mandraffino, G., Minutoli, L., Squadrito, G., and Russo, G.T. (2024). Ketoacidosis and SGLT2 Inhibitors: A Narrative Review. Metabolites, 14.","DOI":"10.3390\/metabo14050264"},{"key":"ref_138","first-page":"e26267","article-title":"SGLT-2 Inhibitor-Associated Euglycemic Diabetic Ketoacidosis: A Case Report and a Literature Review","volume":"14","author":"Mahfooz","year":"2022","journal-title":"Cureus"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1093\/ndt\/gfae060","article-title":"How can inhibition of glucose and sodium transport in the early proximal tubule protect the cardiorenal system?","volume":"39","author":"Vallon","year":"2024","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1111\/dom.13577","article-title":"Sodium-glucose cotransporter 2 inhibitors regulate ketone body metabolism via inter-organ crosstalk","volume":"21","author":"Kim","year":"2018","journal-title":"Diabetes Obes. Metab."},{"key":"ref_141","doi-asserted-by":"crossref","unstructured":"Cai, W., Chong, K., Huang, Y., Huang, C., and Yin, L. (2023). Empagliflozin improves mitochondrial dysfunction in diabetic cardiomyopathy by modulating ketone body metabolism and oxidative stress. Redox Biol., 69.","DOI":"10.2139\/ssrn.4596636"},{"key":"ref_142","doi-asserted-by":"crossref","unstructured":"Dutka, M., Bobi\u0144ski, R., Francuz, T., Garczorz, W., Zimmer, K., Ilczak, T., \u0106wiertnia, M., and Hajduga, M.B. (2022). SGLT-2 Inhibitors in Cancer Treatment\u2014Mechanisms of Action and Emerging New Perspectives. Cancers, 14.","DOI":"10.3390\/cancers14235811"},{"key":"ref_143","doi-asserted-by":"crossref","unstructured":"Mooli, R.G.R., and Ramakrishnan, S.K. (2022). Emerging Role of Hepatic Ketogenesis in Fatty Liver Disease. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.946474"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"4063","DOI":"10.1007\/s00018-016-2280-4","article-title":"Post-translational modifications in mitochondria: Protein signaling in the powerhouse","volume":"73","author":"Stram","year":"2016","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.cmet.2010.11.003","article-title":"SIRT3 Deacetylates Mitochondrial 3-Hydroxy-3-Methylglutaryl CoA Synthase 2 and Regulates Ketone Body Production","volume":"12","author":"Shimazu","year":"2010","journal-title":"Cell Metab."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1111\/j.1432-1033.1990.tb15291.x","article-title":"Glucagon activates mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in vivo by decreasing the extent of succinylation of the enzyme","volume":"187","author":"Quant","year":"1990","journal-title":"Eur. J. Biochem."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.cmet.2013.11.013","article-title":"SIRT5 Regulates the Mitochondrial Lysine Succinylome and Metabolic Networks","volume":"18","author":"Rardin","year":"2013","journal-title":"Cell Metab."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/j.cmet.2012.10.004","article-title":"A Quantitative Map of the Liver Mitochondrial Phosphoproteome Reveals Posttranslational Control of Ketogenesis","volume":"16","author":"Grimsrud","year":"2012","journal-title":"Cell Metab."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1111\/imr.12608","article-title":"Metabolic regulation of NLRP3","volume":"281","author":"Hughes","year":"2017","journal-title":"Immunol. Rev."},{"key":"ref_150","doi-asserted-by":"crossref","unstructured":"Neudorf, H., and Little, J.P. (2023). Impact of fasting & ketogenic interventions on the NLRP3 inflammasome: A narrative review. Biomed. J., 47.","DOI":"10.1016\/j.bj.2023.100677"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.metabol.2015.10.001","article-title":"Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2","volume":"65","author":"Graff","year":"2016","journal-title":"Metabolism"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.pharmthera.2016.04.007","article-title":"Benefits of short-chain fatty acids and their receptors in inflammation and carcinogenesis","volume":"164","author":"Sivaprakasam","year":"2016","journal-title":"Pharmacol. Ther."},{"key":"ref_153","doi-asserted-by":"crossref","unstructured":"Mart\u00edn-Adrados, B., Wculek, S.K., Fern\u00e1ndez-Bravo, S., Torres-Ruiz, R., Valle-Noguera, A., Gomez-S\u00e1nchez, M.J., Hern\u00e1ndez-Walias, J.C., Ferreira, F.M., Corraliza, A.M., and Sancho, D. (2023). Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1185517"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"3964","DOI":"10.4161\/cc.22137","article-title":"Ketone body utilization drives tumor growth and metastasis","volume":"11","author":"Lin","year":"2012","journal-title":"Cell Cycle"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"121827","DOI":"10.1016\/j.lfs.2023.121827","article-title":"Targeting HMG-CoA synthase 2 suppresses tamoxifen-resistant breast cancer growth by augmenting mitochondrial oxidative stress-mediated cell death","volume":"328","author":"Hwang","year":"2023","journal-title":"Life Sci."},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"Lan, Y., Jin, C., Kumar, P., Yu, X., Lenahan, C., and Sheng, J. (2022). Ketogenic Diets and Hepatocellular Carcinoma. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.879205"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.biocel.2017.08.016","article-title":"miR-107-mediated decrease of HMGCS2 indicates poor outcomes and promotes cell migration in hepatocellular carcinoma","volume":"91","author":"Su","year":"2017","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_158","doi-asserted-by":"crossref","unstructured":"Wang, Y.-H., Liu, C.-L., Chiu, W.-C., Twu, Y.-C., and Liao, Y.-J. (2019). HMGCS2 Mediates Ketone Production and Regulates the Proliferation and Metastasis of Hepatocellular Carcinoma. Cancers, 11.","DOI":"10.3390\/cancers11121876"},{"key":"ref_159","doi-asserted-by":"crossref","unstructured":"Ding, R., Chen, T., Zhang, Y., Chen, X., Zhuang, L., and Yang, Z. (2021). HMGCS2 in metabolic pathways was associated with overall survival in hepatocellular carcinoma: A LASSO-derived study. Sci. Prog., 104.","DOI":"10.1177\/00368504211031749"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1158\/1541-7786.MCR-05-0267","article-title":"Ketogenic HMGCS2 Is a c-Myc Target Gene Expressed in Differentiated Cells of Human Colonic Epithelium and Down-Regulated in Colon Cancer","volume":"4","author":"Camarero","year":"2006","journal-title":"Mol. Cancer Res."},{"key":"ref_161","doi-asserted-by":"crossref","unstructured":"Suk, F.-M., Wu, C.-Y., Chiu, W.-C., Chien, C.-Y., Chen, T.-L., and Liao, Y.-J. (2022). HMGCS2 Mediation of Ketone Levels Affects Sorafenib Treatment Efficacy in Liver Cancer Cells. Molecules, 27.","DOI":"10.3390\/molecules27228015"},{"key":"ref_162","doi-asserted-by":"crossref","unstructured":"Suk, F.-M., Wu, C.-Y., Fang, C.-C., Chen, T.-L., and Liao, Y.-J. (2023). \u03b2-HB treatment reverses sorafenib resistance by shifting glycolysis\u2013lactate metabolism in HCC. Biomed. Pharmacother., 166.","DOI":"10.1016\/j.biopha.2023.115293"},{"key":"ref_163","doi-asserted-by":"crossref","unstructured":"Kim, Y., Shin, S.-Y., Jeung, J., Kim, Y., Kang, Y.-W., Lee, S., and Oh, C.-M. (2023). Integrative analysis of mitochondrial metabolic reprogramming in early-stage colon and liver cancer. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1218735"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2019\/8348967","article-title":"Potential Role of HMGCS2 in Tumor Angiogenesis in Colorectal Cancer and Its Potential Use as a Diagnostic Marker","volume":"2019","author":"Zou","year":"2019","journal-title":"Can. J. Gastroenterol. Hepatol."},{"key":"ref_165","doi-asserted-by":"crossref","unstructured":"Mathew, M., Nguyen, N.T., Bhutia, Y.D., Sivaprakasam, S., and Ganapathy, V. (2024). Metabolic Signature of Warburg Effect in Cancer: An Effective and Obligatory Interplay between Nutrient Transporters and Catabolic\/Anabolic Pathways to Promote Tumor Growth. Cancers, 16.","DOI":"10.3390\/cancers16030504"},{"key":"ref_166","first-page":"22460","article-title":"HMGCS2 enhances invasion and metastasis via direct interaction with PPAR\u03b1 to activate Src signaling in colorectal cancer and oral cancer","volume":"8","author":"Chou","year":"2016","journal-title":"Oncotarget"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"152464","DOI":"10.1016\/j.prp.2019.152464","article-title":"HMGCS2 functions as a tumor suppressor and has a prognostic impact in prostate cancer","volume":"215","author":"Wan","year":"2019","journal-title":"Pathol.-Res. Pract."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1074\/mcp.M112.023887","article-title":"Quantitative Proteomics Reveals That Enzymes of the Ketogenic Pathway Are Associated with Prostate Cancer Progression","volume":"12","author":"Saraon","year":"2013","journal-title":"Mol. Cell. Proteom."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12964-019-0505-5","article-title":"Cancer-associated fibroblasts promote prostate tumor growth and progression through upregulation of cholesterol and steroid biosynthesis","volume":"18","author":"Neuwirt","year":"2020","journal-title":"Cell Commun. Signal."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.2174\/1570159X20666220830102628","article-title":"Ketogenic Diet: An Effective Treatment Approach for Neurodegenerative Diseases","volume":"20","author":"Zhang","year":"2022","journal-title":"Curr. Neuropharmacol."},{"key":"ref_171","doi-asserted-by":"crossref","unstructured":"W\u0142odarek, D. (2019). Role of Ketogenic Diets in Neurodegenerative Diseases (Alzheimer\u2019s Disease and Parkinson\u2019s Disease). Nutrients, 11.","DOI":"10.3390\/nu11010169"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"640","DOI":"10.2174\/1566524021666211004104703","article-title":"Ketogenic Diet: A Promising Neuroprotective Composition for Managing Alzheimer\u2019s Diseases and its Pathological Mechanisms","volume":"22","author":"Sridharan","year":"2022","journal-title":"Curr. Mol. Med."},{"key":"ref_173","doi-asserted-by":"crossref","unstructured":"Dy\u0144ka, D., Kowalcze, K., and Paziewska, A. (2022). The Role of Ketogenic Diet in the Treatment of Neurological Diseases. Nutrients, 14.","DOI":"10.3390\/nu14235003"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.semcdb.2019.05.004","article-title":"Microglia-mediated neuroinflammation in neurodegenerative diseases","volume":"94","author":"Subhramanyam","year":"2019","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_175","doi-asserted-by":"crossref","unstructured":"Polito, R., La Torre, M.E., Moscatelli, F., Cibelli, G., Valenzano, A., Panaro, M.A., Monda, M., Messina, A., Monda, V., and Pisanelli, D. (2023). The Ketogenic Diet and Neuroinflammation: The Action of Beta-Hydroxybutyrate in a Microglial Cell Line. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043102"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.gene.2014.08.016","article-title":"Genotype-based databases for variants causing rare diseases","volume":"550","author":"Lanthaler","year":"2014","journal-title":"Gene"},{"key":"ref_177","unstructured":"(2025, February 27). Available online: http:\/\/databases.lovd.nl\/shared\/genes."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.ejmg.2013.05.008","article-title":"New case of mitochondrial HMG-CoA synthase deficiency. Functional analysis of eight mutations","volume":"56","author":"Ramos","year":"2013","journal-title":"Eur. J. Med Genet."},{"key":"ref_179","doi-asserted-by":"crossref","unstructured":"Puisac, B., Marcos-Alcalde, I., Hern\u00e1ndez-Marcos, M., Morlana, P.T., Levtova, A., Schwahn, B.C., DeLaet, C., Lace, B., G\u00f3mez-Puertas, P., and Pi\u00e9, J. (2018). Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme Dimerization Surface and Characterization of Three New Patients. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19041010"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1002\/ped4.12130","article-title":"Novel HMGCS2 pathogenic variants in a Chinese family with mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency","volume":"3","author":"Zhang","year":"2019","journal-title":"Pediatr. Investig."},{"key":"ref_181","first-page":"19","article-title":"A Japanese case of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency who presented with severe metabolic acidosis and fatty liver without hypoglycemia","volume":"48","author":"Lee","year":"2019","journal-title":"JIMD Rep."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1002\/ajmg.a.61590","article-title":"Expanding the clinical spectrum of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency with Turkish cases harboring novel HMGCS2 gene mutations and literature review","volume":"182","author":"Kilic","year":"2020","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"39","DOI":"10.3892\/etm.2020.9166","article-title":"Japanese patients with mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: In vitro functional analysis of five novel HMGCS2 mutations","volume":"20","author":"Ago","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.cca.2020.04.004","article-title":"Clinical, biochemical, molecular and therapeutic characteristics of four new patients of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency","volume":"509","author":"Wang","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"104086","DOI":"10.1016\/j.ejmg.2020.104086","article-title":"Expanding phenotypic and mutational spectra of mitochondrial HMG-CoA synthase deficiency","volume":"63","author":"Rojnueangnit","year":"2020","journal-title":"Eur. J. Med. Genet."},{"key":"ref_186","doi-asserted-by":"crossref","unstructured":"Wu, S., Shen, L., Chen, Q., Gong, C., Yang, Y., Wei, H., Cao, B., and Chen, Y. (2022). Clinical, Biochemical, Molecular, and Outcome Features of Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency in 10 Chinese Patients. Front. Genet., 12.","DOI":"10.3389\/fgene.2021.816779"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"e257011","DOI":"10.1136\/bcr-2023-257011","article-title":"Mitochondrial 3-hydroxymethylglutaryl-CoA synthase-2 (HMGCS2) deficiency: A rare case with bicytopenia and coagulopathy","volume":"16","author":"Wali","year":"2023","journal-title":"BMJ Case Rep."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"109007","DOI":"10.1016\/j.ymgme.2024.109007","article-title":"Mitochondrial HMG-CoA synthase deficiency","volume":"144","author":"Decru","year":"2024","journal-title":"Mol. Genet. Metab."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"e13833","DOI":"10.1111\/acel.13833","article-title":"Ketone bodies: A double-edged sword for mammalian life span","volume":"22","author":"Tomita","year":"2023","journal-title":"Aging Cell"},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1042\/bj2850647","article-title":"Metabolism of R- and S-1,3-butanediol in perfused livers from meal-fed and starved rats","volume":"285","author":"Desrochers","year":"1992","journal-title":"Biochem. J."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1056\/NEJM199710233371704","article-title":"Fasting Hypoketotic Coma in a Child with Deficiency of Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase","volume":"337","author":"Thompson","year":"1997","journal-title":"N. Engl. J. Med."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/4\/580\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:14:26Z","timestamp":1760030066000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/4\/580"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,14]]},"references-count":191,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["biom15040580"],"URL":"https:\/\/doi.org\/10.3390\/biom15040580","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,14]]}}}