{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HCAR1 (also known as GPR81) is an endogenous G protein–coupled receptor for lactate that acts as a metabolic sensor linking extracellular lactate levels to diverse intracellular signaling pathways. In adipocytes, activation of HCAR1 by lactate couples to Gi proteins to suppress adenylyl cyclase activity, thereby mediating potent antilipolytic effects and contributing to energy homeostasis and the regulation of circulating free fatty acids."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition to its metabolic role, HCAR1 has been implicated in tumor biology; its activation in cancer cells modulates key adaptive processes such as the upregulation of drug transporters and DNA repair proteins, which together contribute to chemoresistance and enhanced cell survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Furthermore, in hepatocellular carcinoma, interference with lactate uptake through HCAR1 can promote ferroptosis by altering energy sensing and lipid metabolism"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", while in breast cancer, HCAR1 signaling supports tumor growth and angiogenesis via downstream activation of pathways that regulate immune checkpoint expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Beyond cancer, HCAR1 expressed in the central nervous system and sensory tissues has been shown to mediate lactate’s nonmetabolic effects. In the ischemic brain, for example, antagonism of HCAR1 reduces neuronal death by modulating stress-responsive mitogen-activated protein kinases"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", and in the retina, lactate acting via HCAR1 in Müller cells promotes angiogenic factor production needed for proper vascular network formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Finally, studies in the hypothalamus reveal that although HCAR1 is not present in proopiomelanocortin neurons themselves, lactate signaling through HCAR1 localized on astrocytes modulates neuronal activity and may influence systemic metabolic responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Collectively, these findings underscore how HCAR1 integrates lactate metabolism with regulation of lipid mobilization, cell survival, DNA repair, angiogenesis, and neuroprotection—highlighting its therapeutic potential in metabolic disorders, cancer, and ischemic injuries.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ellen H Jeninga, Anne Bugge, Ronni Nielsen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Peroxisome proliferator-activated receptor gamma regulates expression of the anti-lipolytic G-protein-coupled receptor 81 (GPR81/Gpr81)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.040741"}], "href": "https://doi.org/10.1074/jbc.M109.040741"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19633298"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19633298"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Taku Sakurai, Richard Davenport, Stuart Stafford, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of a novel GPR81-selective agonist that suppresses lipolysis in mice without cutaneous flushing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Pharmacol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejphar.2014.01.029"}], "href": "https://doi.org/10.1016/j.ejphar.2014.01.029"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24486398"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24486398"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "W Wagner, K D Kania, A Blauz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The lactate receptor (HCAR1/GPR81) contributes to doxorubicin chemoresistance via ABCB1 transporter up-regulation in human cervical cancer HeLa cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Physiol Pharmacol (2017)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29151072"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29151072"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Waldemar Wagner, Katarzyna D Kania, Wojciech M Ciszewski "}, {"type": "b", "children": [{"type": "t", "text": "Stimulation of lactate receptor (HCAR1) affects cellular DNA repair capacity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "DNA Repair (Amst) (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.dnarep.2017.02.007"}], "href": "https://doi.org/10.1016/j.dnarep.2017.02.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28258841"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28258841"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Youbo Zhao, Menghuan Li, Xuemei Yao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HCAR1/MCT1 Regulates Tumor Ferroptosis through the Lactate-Mediated AMPK-SCD1 Activity and Its Therapeutic Implications."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2020.108487"}], "href": "https://doi.org/10.1016/j.celrep.2020.108487"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33296645"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33296645"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Yu Jin Lee, Kyeong Jin Shin, Soo-Ah Park, et al. "}, {"type": "b", "children": [{"type": "t", "text": "G-protein-coupled receptor 81 promotes a malignant phenotype in breast cancer through angiogenic factor secretion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.12286"}], "href": "https://doi.org/10.18632/oncotarget.12286"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27765922"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27765922"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Zhe Shen, Lei Jiang, Yang Yuan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of G protein-coupled receptor 81 (GPR81) protects against ischemic brain injury."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "CNS Neurosci Ther (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cns.12362"}], "href": "https://doi.org/10.1111/cns.12362"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25495836"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25495836"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Ankush Madaan, Prabhas Chaudhari, Mathieu Nadeau-Vallée, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Müller Cell-Localized G-Protein-Coupled Receptor 81 (Hydroxycarboxylic Acid Receptor 1) Regulates Inner Retinal Vasculature via Norrin/Wnt Pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajpath.2019.05.016"}], "href": "https://doi.org/10.1016/j.ajpath.2019.05.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31220454"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31220454"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "P Órdenes, P S Villar, E Tarifeño-Saldivia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Lactate activates hypothalamic POMC neurons by intercellular signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-021-00947-7"}], "href": "https://doi.org/10.1038/s41598-021-00947-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34737351"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34737351"}]}]}]}