Hcar1, short for hydroxycarboxylic acid receptor 1, is a G-coupled protein receptor (GPCR) belonging to class A and coupled to Gαi. It serves as the receptor for lactate, a metabolite that has multiple functions in the body. HCAR1 is involved in diverse biological processes by reducing cellular cAMP and downstream Gβγ signaling. It has been implicated in neural activities, angiogenesis, inflammation, and cancer pathogenesis [5].

In neonatal hypoxia-ischemia (HI) mouse models, HCAR1 knockout mice showed reduced tissue regeneration compared to wild-type mice. Proliferation of neural progenitor and glial cells, along with microglial activation, was impaired. Transcriptome analysis revealed a strong transcriptional response to HI in wild-type mice, while the knockout mice had a modest response, with dysregulation in fundamental tissue-repair processes like the cell cycle and innate immunity. This suggests HCAR1 is a key transcriptional regulator of pathways promoting tissue regeneration after HI [1]. In HCC cells, blocking lactate uptake via HCAR1/MCT1 inhibition promotes ferroptosis, indicating its role in regulating tumor ferroptosis [2]. In osteoarthritis, lactate-mediated chondrocyte damage is related to HCAR1-induced up-regulation of NOX4 expression [3]. Exercise-induced cerebral VEGF and angiogenesis are via HCAR1, as high-intensity interval exercise or lactate injection increases brain VEGFA and capillary density in wild-type but not HCAR1 knockout mice [4].

In conclusion, HCAR1 is a crucial receptor in lactate-mediated signaling. Model-based research, especially using HCAR1 knockout mouse models, has revealed its significant roles in multiple disease areas such as neonatal HI-induced brain injury, tumor ferroptosis, osteoarthritis, and exercise-related cerebral angiogenesis. Understanding HCAR1 provides insights into potential therapeutic targets for these diseases.

References:

1. Kennedy, Lauritz, Glesaaen, Emilie R, Palibrk, Vuk, Bjørås, Magnar, Rinholm, Johanne E. 2022. Lactate receptor HCAR1 regulates neurogenesis and microglia activation after neonatal hypoxia-ischemia. In eLife, 11, . doi:10.7554/eLife.76451. https://pubmed.ncbi.nlm.nih.gov/35942676/

2. Zhao, Youbo, Li, Menghuan, Yao, Xuemei, Zhao, Yanli, Luo, Zhong. . HCAR1/MCT1 Regulates Tumor Ferroptosis through the Lactate-Mediated AMPK-SCD1 Activity and Its Therapeutic Implications. In Cell reports, 33, 108487. doi:10.1016/j.celrep.2020.108487. https://pubmed.ncbi.nlm.nih.gov/33296645/

3. Huang, Yi-Fan, Wang, Guan, Ding, Lu, Li, Xia, Qi, Xin. 2023. Lactate-upregulated NADPH-dependent NOX4 expression via HCAR1/PI3K pathway contributes to ROS-induced osteoarthritis chondrocyte damage. In Redox biology, 67, 102867. doi:10.1016/j.redox.2023.102867. https://pubmed.ncbi.nlm.nih.gov/37688977/

4. Morland, Cecilie, Andersson, Krister A, Haugen, Øyvind P, Storm-Mathisen, Jon, Bergersen, Linda H. 2017. Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1. In Nature communications, 8, 15557. doi:10.1038/ncomms15557. https://pubmed.ncbi.nlm.nih.gov/28534495/

5. Mohammad Nezhady, Mohammad Ali, Modaresinejad, Monir, Zia, Aliabbas, Chemtob, Sylvain. 2023. Versatile lactate signaling via HCAR1: a multifaceted GPCR involved in many biological processes. In American journal of physiology. Cell physiology, 325, C1502-C1515. doi:10.1152/ajpcell.00346.2023. https://pubmed.ncbi.nlm.nih.gov/37899751/