β-hydroxybutyrate: A crucial therapeutic target for diverse liver diseases

Wei, 2022, β-hydroxybutyrate in cardiovascular diseases a minor metabolite of great expectations, Front. Mol. Biosci., 9, 10.3389/fmolb.2022.823602 Puchalska, 2017, Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics, Cell Metab., 25, 262, 10.1016/j.cmet.2016.12.022 Achanta, 2017, β-hydroxybutyrate in the brain: one molecule, multiple mechanisms, Neurochem. Res., 42, 35, 10.1007/s11064-016-2099-2 Yang, 2022, Intermittent fasting-a healthy dietary pattern for diabetic nephropathy, Nutrients, 14, 10.3390/nu14193995 Koutnik, 2019, Anticatabolic effects of ketone bodies in skeletal muscle, Trends Endocrinol. Metab., 30, 227, 10.1016/j.tem.2019.01.006 Feng, 2019, Multi-dimensional roles of ketone bodies in cancer biology: opportunities for cancer therapy, Pharmacol. Res., 150, 10.1016/j.phrs.2019.104500 Orii, 2008, Liver-specific silencing of the human gene encoding succinyl-CoA: 3-ketoacid CoA transferase, Tohoku J. Exp. Med., 215, 227, 10.1620/tjem.215.227 Halestrap, 2004, The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond, Pflug. Arch., 447, 619, 10.1007/s00424-003-1067-2 Glew, 2010, You can get there from here: acetone, anionic ketones and even-carbon fatty acids can provide substrates for gluconeogenesis, Niger. J. Physiol. Sci., 25, 2 Cheng, 2019, Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet, Cell, 178, 1115, 10.1016/j.cell.2019.07.048 Adijanto, 2014, The retinal pigment epithelium utilizes fatty acids for ketogenesis, J. Biol. Chem., 289, 20570, 10.1074/jbc.M114.565457 Zhang, 2011, Proteomics analysis reveals diabetic kidney as a ketogenic organ in type 2 diabetes, Am. J. Physiol. Endocrinol. Metab., 300, E287, 10.1152/ajpendo.00308.2010 Takahashi, 2014, Roles and regulation of ketogenesis in cultured astroglia and neurons under hypoxia and hypoglycemia, ASN Neuro, 6, 10.1177/1759091414550997 Stagg, 2021, Diminished ketone interconversion, hepatic TCA cycle flux, and glucose production in D-β-hydroxybutyrate dehydrogenase hepatocyte-deficient mice, Mol. Metab., 53, 10.1016/j.molmet.2021.101269 Nasser, 2022, Ketogenic diet administration to mice after a high-fat-diet regimen promotes weight loss, glycemic normalization and induces adaptations of ketogenic pathways in liver and kidney, Mol. Metab., 65, 10.1016/j.molmet.2022.101578 Venable, 2022, Fasting-induced HMGCS2 expression in the kidney does not contribute to circulating ketones, Am. J. Physiol. Ren. Physiol., 322, F460, 10.1152/ajprenal.00447.2021 Balasse, 1989, Ketone body production and disposal: effects of fasting, diabetes, and exercise, Diabetes Metab. Rev., 5, 247, 10.1002/dmr.5610050304 Wang, 2021, β-hydroxybutyrate as an anti-aging metabolite, Nutrients, 13, 10.3390/nu13103420 Owen, 1967, Brain metabolism during fasting, J. Clin. Invest, 46, 1589, 10.1172/JCI105650 Sultan, 1988, D-3-hydroxybutyrate metabolism in the perfused rat heart, Mol. Cell. Biochem., 79, 113, 10.1007/BF02424552 Guder, 1986, Metabolic fuels along the nephron: pathways and intracellular mechanisms of interaction, Kidney Int, 29, 41, 10.1038/ki.1986.6 Takahashi, 2019, Effects of β-hydroxybutyrate treatment on glycogen repletion and its related signaling cascades in epitrochlearis muscle during 120 min of postexercise recovery, Appl. Physiol. Nutr. Metab., 44, 1311, 10.1139/apnm-2018-0860 Lee, 2020, β-hydroxybutyrate suppresses lipid accumulation in aged liver through GPR109A-mediated signaling, Aging Dis., 11, 777, 10.14336/AD.2019.0926 Kimura, 2011, Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41), Proc. Natl. Acad. Sci. U. S. A, 108, 8030, 10.1073/pnas.1016088108 Lund, 2015, The metabolic impact of β-hydroxybutyrate on neurotransmission: Reduced glycolysis mediates changes in calcium responses and KATP channel receptor sensitivity, J. Neurochem., 132, 520, 10.1111/jnc.12975 Juge, 2010, Metabolic control of vesicular glutamate transport and release, Neuron, 68, 99, 10.1016/j.neuron.2010.09.002 Mikami, 2020, β-Hydroxybutyrate enhances the cytotoxic effect of cisplatin via the inhibition of HDAC/survivin axis in human hepatocellular carcinoma cells, J. Pharmacol. Sci., 142, 1, 10.1016/j.jphs.2019.10.007 Zhou, 2022, Function and mechanism of histone β-hydroxybutyrylation in health and disease, Front. Immunol., 13 Li, 2021, β-Hydroxybutyrate inhibits histone deacetylase 3 to promote claudin-5 generation and attenuate cardiac microvascular hyperpermeability in diabetes, Diabetologia, 64, 226, 10.1007/s00125-020-05305-2 Shimazu, 2013, Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor, Science, 339, 211, 10.1126/science.1227166 Sangalli, 2018, Metabolic gene expression and epigenetic effects of the ketone body β-hydroxybutyrate on H3K9ac in bovine cells, oocytes and embryos, Sci. Rep., 8, 13766, 10.1038/s41598-018-31822-7 Chriett, 2019, Prominent action of butyrate over β-hydroxybutyrate as histone deacetylase inhibitor, transcriptional modulator and anti-inflammatory molecule, Sci. Rep., 9, 742, 10.1038/s41598-018-36941-9 Seitz, 2018, Alcoholic liver disease, Nat. Rev. Dis. Prim., 4, 16, 10.1038/s41572-018-0014-7 Kong, 2019, Pathogenesis, early diagnosis, and therapeutic management of alcoholic liver disease, Int. J. Mol. Sci., 20, 10.3390/ijms20112712 Peng, 2009, Adenosine signaling contributes to ethanol-induced fatty liver in mice, J. Clin. Invest, 119, 582, 10.1172/JCI37409 Chen, 2018, β-Hydroxybutyrate protects from alcohol-induced liver injury via a Hcar2-cAMP dependent pathway, J. Hepatol., 69, 687, 10.1016/j.jhep.2018.04.004 Lin, 2016, Transcriptome-wide analysis reveals modulation of human macrophage inflammatory phenotype through alternative splicing, Arterioscler. Thromb. Vasc. Biol., 36, 1434, 10.1161/ATVBAHA.116.307573 Arabpour, 2021, Anti-inflammatory and M2 macrophage polarization-promoting effect of mesenchymal stem cell-derived exosomes, Int. Immunopharmacol., 97, 10.1016/j.intimp.2021.107823 Wiers, 2021, Ketogenic diet reduces alcohol withdrawal symptoms in humans and alcohol intake in rodents, Sci. Adv., 7, 10.1126/sciadv.abf6780 Friedman, 2018, Mechanisms of NAFLD development and therapeutic strategies, Nat. Med., 24, 908, 10.1038/s41591-018-0104-9 Younossi, 2019, Non-alcoholic fatty liver disease - a global public health perspective, J. Hepatol., 70, 531, 10.1016/j.jhep.2018.10.033 Ipsen, 2018, Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease, Cell. Mol. Life Sci., 75, 3313, 10.1007/s00018-018-2860-6 Williamson, 1969, Control mechanisms of gluconeogenesis and ketogenesis. II. Interactions between fatty acid oxidation and the citric acid cycle in perfused rat liver, J. Biol. Chem., 244, 4617, 10.1016/S0021-9258(18)93669-0 Cotter, 2014, Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia, J. Clin. Invest, 124, 5175, 10.1172/JCI76388 Chalasani, 2003, Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis, Hepatology, 37, 544, 10.1053/jhep.2003.50095 Bugianesi, 2005, Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms, Diabetologia, 48, 634, 10.1007/s00125-005-1682-x Wang, 2021, High‑fat diet‑induced fatty liver is associated with immunosuppressive response during sepsis in mice, Oxid. Med. Cell. Longev., 2021, 10.1155/2021/5833857 Sanyal, 2001, Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities, Gastroenterology, 120, 1183, 10.1053/gast.2001.23256 Kotronen, 2009, Liver fat and lipid oxidation in humans, Liver Int., 29, 1439, 10.1111/j.1478-3231.2009.02076.x Benedict, 2017, Non-alcoholic fatty liver disease: an expanded review, World J. Hepatol., 9, 715, 10.4254/wjh.v9.i16.715 Inokuchi, 1992, Resistance to ketosis in moderately obese patients: influence of fatty liver, Intern. Med., 31, 978, 10.2169/internalmedicine.31.978 Croci, 2013, Whole-body substrate metabolism is associated with disease severity in patients with non-alcoholic fatty liver disease, Gut, 62, 1625, 10.1136/gutjnl-2012-302789 Fletcher, 2019, Impaired ketogenesis and increased acetyl-CoA oxidation promote hyperglycemia in human fatty liver, JCI Insight, 5 Mey, 2020, β-Hydroxybutyrate is reduced in humans with obesity-related NAFLD and displays a dose-dependent effect on skeletal muscle mitochondrial respiration in vitro, Am. J. Physiol. Endocrinol. Metab., 319, E187, 10.1152/ajpendo.00058.2020 Cabré, 2020, Plasma metabolic alterations in patients with severe obesity and non-alcoholic steatohepatitis, Aliment. Pharmacol. Ther., 51, 374, 10.1111/apt.15606 Brunt, 2001, Nonalcoholic steatohepatitis: definition and pathology, Semin. Liver Dis., 21, 3, 10.1055/s-2001-12925 Männistö, 2015, Ketone body production is differentially altered in steatosis and non-alcoholic steatohepatitis in obese humans, Liver Int., 35, 1853, 10.1111/liv.12769 Mooli, 2022, Emerging Role of Hepatic Ketogenesis in Fatty Liver Disease, Front. Physiol., 13, 10.3389/fphys.2022.946474 Xu, 2022, Bdh1 overexpression ameliorates hepatic injury by activation of Nrf2 in a MAFLD mouse model, Cell Death Discov., 8, 49, 10.1038/s41420-022-00840-w Otsuka, 2020, Deficiency of 3-hydroxybutyrate dehydrogenase (BDH1) in mice causes low ketone body levels and fatty liver during fasting, J. Inherit. Metab. Dis., 43, 960, 10.1002/jimd.12243 d'Avignon, 2018, Hepatic ketogenic insufficiency reprograms hepatic glycogen metabolism and the lipidome, JCI Insight, 3 Youm, 2015, The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease, Nat. Med., 21, 263, 10.1038/nm.3804 Spigoni, 2022, Activation of G protein-coupled receptors by ketone bodies: clinical implication of the ketogenic diet in metabolic disorders, Front. Endocrinol. (Lausanne), 13, 10.3389/fendo.2022.972890 Stec, 2019, Loss of hepatic PPARα promotes inflammation and serum hyperlipidemia in diet-induced obesity, Am. J. Physiol. Regul. Integr. Comp. Physiol., 317, R733, 10.1152/ajpregu.00153.2019 Hinds JR, 2020, Bilirubin nanoparticles reduce diet-induced hepatic steatosis, improve fat utilization, and increase plasma β-hydroxybutyrate, Front. Pharmacol., 11, 10.3389/fphar.2020.594574 Piñero, 2020, Biomarkers in hepatocellular carcinoma: diagnosis, prognosis and treatment response assessment, Cells, 9, 10.3390/cells9061370 Vogel, 2022, Hepatocellular carcinoma, Lancet, 400, 1345, 10.1016/S0140-6736(22)01200-4 Gyamfi, 2022, Cancer as a metabolic disorder, Int. J. Mol. Sci., 23, 10.3390/ijms23031155 Seyfried, 2014, Cancer as a metabolic disease: implications for novel therapeutics, Carcinogenesis, 35, 515, 10.1093/carcin/bgt480 Dąbek, 2020, Modulation of cellular biochemistry, epigenetics and metabolomics by ketone bodies. implications of the ketogenic diet in the physiology of the organism and pathological states, Nutrients, 12, 10.3390/nu12030788 Weber, 2020, Ketogenic diet in the treatment of cancer - Where do we stand?, Mol. Metab., 33, 102, 10.1016/j.molmet.2019.06.026 Zhang, 2021, MTA2 triggered R-loop trans-regulates BDH1-mediated β-hydroxybutyrylation and potentiates propagation of hepatocellular carcinoma stem cells, Signal Transduct. Target. Ther., 6, 135, 10.1038/s41392-021-00464-z Liu, 2021, Expression and clinical significance of BDH1 in liver cancer, Med. (Baltim. ), 100 Zhang, 1989, Regulation of D-beta-hydroxybutyrate dehydrogenase in rat hepatoma cell lines, Cancer Res, 49, 2433 Suk, 2022, HMGCS2 mediation of ketone levels affects sorafenib treatment efficacy in liver cancer cells, Molecules, 27, 10.3390/molecules27228015 Wakana, 2019, Effects of medium-chain triglycerides administration in chemically-induced carcinogenesis in mice, Anticancer Res, 39, 6653, 10.21873/anticanres.13880 Wang, 2019, HMGCS2 mediates ketone production and regulates the proliferation and metastasis of hepatocellular carcinoma, Cancers (Basel), 11, 10.3390/cancers11121876 Cui, 2022, HMGCL-induced β-hydroxybutyrate production attenuates hepatocellular carcinoma via DPP4-mediated ferroptosis susceptibility, Hepatol. Int. Bae, 2016, β-Hydroxybutyrate suppresses inflammasome formation by ameliorating endoplasmic reticulum stress via AMPK activation, Oncotarget, 7, 66444, 10.18632/oncotarget.12119 Wei, 2021, Endoplasmic reticulum stress signaling and the pathogenesis of hepatocarcinoma, Int. J. Mol. Sci., 22 Lin, 2019, Cancer and ER stress: mutual crosstalk between autophagy, oxidative stress and inflammatory response, Biomed. Pharmacother., 118, 10.1016/j.biopha.2019.109249 Villanueva, 2016, The transition from inflammation to cancer in the liver, Clin. Liver Dis. (Hoboken), 8, 89, 10.1002/cld.578 Yang, 2018, Predictive and preventive significance of AMPK activation on hepatocarcinogenesis in patients with liver cirrhosis, Cell Death Dis., 9, 264, 10.1038/s41419-018-0308-4 Tagawa, 2019, β-hydroxybutyrate protects hepatocytes against endoplasmic reticulum stress in a sirtuin 1-independent manner, Arch. Biochem. Biophys., 663, 220, 10.1016/j.abb.2019.01.020 Thorrez, 2011, Tissue-specific disallowance of housekeeping genes: the other face of cell differentiation, Genome Res., 21, 95, 10.1101/gr.109173.110 Huang, 2016, Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress, Cell Res, 26, 1112, 10.1038/cr.2016.109 Dar, 2019, Ischaemia reperfusion injury in liver transplantation: cellular and molecular mechanisms, Liver Int., 39, 788, 10.1111/liv.14091 Liu, 2021, New insights in mechanisms and therapeutics for short- and long-term impacts of hepatic ischemia reperfusion injury post liver transplantation, Int. J. Mol. Sci., 22 Makievskaya, 2023, Ketogenic diet and ketone bodies against ischemic injury: targets, mechanisms, and therapeutic potential, Int. J. Mol. Sci., 24, 10.3390/ijms24032576 Menezes-Filho, 2017, Caloric restriction protects livers from ischemia/reperfusion damage by preventing Ca(2+)-induced mitochondrial permeability transition, Free Radic. Biol. Med., 110, 219, 10.1016/j.freeradbiomed.2017.06.013 Ren, 2019, Alteration in gut microbiota caused by time-restricted feeding alleviate hepatic ischaemia reperfusion injury in mice, J. Cell. Mol. Med, 23, 1714, 10.1111/jcmm.14069 Miyauchi, 2019, Up-regulation of FOXO1 and reduced inflammation by β-hydroxybutyric acid are essential diet restriction benefits against liver injury, Proc. Natl. Acad. Sci. U. S. A., 116, 13533, 10.1073/pnas.1820282116 Kaltenmeier, 2022, Role of immuno-inflammatory signals in liver ischemia-reperfusion injury, Cells, 11, 10.3390/cells11142222 Jiménez-Castro, 2019, Inflammasome-mediated inflammation in liver ischemia-reperfusion injury, Cells, 8, 10.3390/cells8101131 Zhang, 2021, The role of mitochondria in liver ischemia-reperfusion injury: from aspects of mitochondrial oxidative stress, mitochondrial fission, mitochondrial membrane permeable transport pore formation, mitophagy, and mitochondria-related protective measures, Oxid. Med. Cell. Longev., 2021 Semmler, 2023, Eating, diet, and nutrition for the treatment of non-alcoholic fatty liver disease, Clin. Mol. Hepatol., 29, S244, 10.3350/cmh.2022.0364 de Castro-de-Paiva, 2022, Intermittent fasting, high-intensity interval training, or a combination of both have beneficial effects in obese mice with nonalcoholic fatty liver disease, J. Nutr. Biochem, 104, 10.1016/j.jnutbio.2022.108997 Yin, 2021, Effect of intermittent fasting on non-alcoholic fatty liver disease: systematic review and meta-analysis, Front. Nutr., 8, 10.3389/fnut.2021.709683 Faris, 2021, The effects of Ramadan intermittent fasting on liver function in healthy adults: a systematic review, meta-analysis, and meta-regression, Diabetes Res. Clin. Pract., 178, 10.1016/j.diabres.2021.108951 Minciuna, 2022, Is fasting good when one is at risk of liver cancer?, Cancers, 14, 10.3390/cancers14205084 Sarkar, 2023, Intermittent fasting induces rapid hepatocyte proliferation to restore the hepatostat in the mouse liver, Elife, 12, 10.7554/eLife.82311 Michalopoulos, 2021, Novel insights into liver homeostasis and regeneration, Nat. Rev. Gastroenterol. Hepatol., 18, 369, 10.1038/s41575-021-00454-0 McCay, 1989, The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935, Nutrition, 5, 155 Chimienti, 2021, The age-sensitive efficacy of calorie restriction on mitochondrial biogenesis and mtDNA damage in rat liver, Int. J. Mol. Sci., 22, 10.3390/ijms22041665 Teofilović, 2022, Late-onset calorie restriction improves lipid metabolism and aggravates inflammation in the liver of old wistar rats, Front. Nutr., 9, 10.3389/fnut.2022.899255 Johari, 2019, A randomised controlled trial on the effectiveness and adherence of modified alternate-day calorie restriction in improving activity of non-alcoholic fatty liver disease, Sci. Rep., 9, 11232, 10.1038/s41598-019-47763-8 Ristic-Medic, 2020, Calorie-restricted mediterranean and low-fat diets affect fatty acid status in individuals with nonalcoholic fatty liver disease, Nutrients, 13, 10.3390/nu13010015 Moore, 2020, A fad too far? Dietary strategies for the prevention and treatment of NAFLD, Obesity, 28, 1843, 10.1002/oby.22964 Wolf, 2019, Impact of a preoperative low-calorie diet on liver histology in patients with fatty liver disease undergoing bariatric surgery, Surg. Obes. Relat. Dis., 15, 1766, 10.1016/j.soard.2019.08.013 Negri, 2020, ), J. Clin. Med., 9 Luukkonen, 2020, Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease, Proc. Natl. Acad. Sci. U. S. A, 117, 7347, 10.1073/pnas.1922344117 McKenzie, 2021, Type 2 diabetes prevention focused on normalization of glycemia: a two-year pilot study, Nutrients, 13, 10.3390/nu13030749 O'Neill, 2020, The ketogenic diet: pros and cons, Atherosclerosis, 292, 119, 10.1016/j.atherosclerosis.2019.11.021 Li, 2021, SLC38A4 functions as a tumour suppressor in hepatocellular carcinoma through modulating Wnt/β-catenin/MYC/HMGCS2 axis, Br. J. Cancer, 125, 865, 10.1038/s41416-021-01490-y Lan, 2022, Ketogenic Diets and Hepatocellular Carcinoma, Front. Oncol., 12, 10.3389/fonc.2022.879205 Healy, 2015, Dietary effects on liver tumor burden in mice treated with the hepatocellular carcinogen diethylnitrosamine, J. Hepatol., 62, 599, 10.1016/j.jhep.2014.10.024 Byrne, 2018, Serial MRI imaging reveals minimal impact of ketogenic diet on established liver tumor growth, Cancers, 10, 10.3390/cancers10090312 Mierziak, 2021, 3-hydroxybutyrate as a metabolite and a signal molecule regulating processes of living organisms, Biomolecules, 11, 10.3390/biom11030402 Vieira, 2022, Time-restricted feeding combined with aerobic exercise training can prevent weight gain and improve metabolic disorders in mice fed a high-fat diet, J. Physiol., 600, 797, 10.1113/JP280820 Zelber-Sagi, 2022, One size does not fit all; practical, personal tailoring of the diet to NAFLD patients, Liver Int., 42, 1731, 10.1111/liv.15335 Saeed, 2019, Evaluation of dietary approaches for the treatment of non-alcoholic fatty liver disease: a systematic review, Nutrients, 11, 10.3390/nu11123064 Soto-Mota, 2020, Why a d-β-hydroxybutyrate monoester?, Biochem. Soc. Trans., 48, 51, 10.1042/BST20190240 Stubbs, 2021, In vitro stability and in vivo pharmacokinetics of the novel ketogenic ester, bis hexanoyl (R)-1,3-butanediol, Food Chem. Toxicol., 147, 10.1016/j.fct.2020.111859 Brunengraber, 1997, Potential of ketone body esters for parenteral and oral nutrition, Nutrition, 13, 233, 10.1016/S0899-9007(96)00409-1 Veech, 2004, The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism, Prostaglandins Leukot. Essent. Fat. Acids, 70, 309, 10.1016/j.plefa.2003.09.007 Newman, 2017, β-hydroxybutyrate: a signaling metabolite, Annu. Rev. Nutr., 37, 51, 10.1146/annurev-nutr-071816-064916 Hazem, 2018, Comparison of lactate and β-hydroxybutyrate in the treatment of concanavalin-A induced hepatitis, Int. Immunopharmacol., 61, 376, 10.1016/j.intimp.2018.06.026 Schönfeld, 2016, Short- and medium-chain fatty acids in energy metabolism: the cellular perspective, J. Lipid Res, 57, 943, 10.1194/jlr.R067629 Larsen, 2005, Fluorometric determination of beta-hydroxybutyrate in milk and blood plasma, J. Dairy Sci., 88, 2004, 10.3168/jds.S0022-0302(05)72876-9 Møller, 2020, Ketone body, 3-hydroxybutyrate: minor metabolite - major medical manifestations, J. Clin. Endocrinol. Metab., 105, 10.1210/clinem/dgaa370