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Last update 23 Jan 2025

HCAR1

Last update 23 Jan 2025

Basic Info

Synonyms

FKSG80, G protein-coupled receptor 104, G protein-coupled receptor 81

+ [10]

Introduction

Acts as a receptor for L-lactate and mediates its anti-lipolytic effect through a G(i)-protein-mediated pathway.

Drugs associated with HCAR1

Dual GPR81/GPR109A agonist

Target

HCAR1 x NIACR1

Mechanism

HCAR1 agonists [+1]

Active Org.

AstraZeneca PLC

Originator Org.

AstraZeneca PLC

Active Indication

Obesity

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

HCAR1 antagonists(SOLID)

Target

HCAR1

Mechanism

HCAR1 agonists

Active Org.

University of Copenhagen [+1]

Originator Org.

University of Copenhagen [+1]

Active Indication

Solid tumor

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with HCAR1

100 Translational Medicine associated with HCAR1

0 Patents (Medical) associated with HCAR1

281

Literatures (Medical) associated with HCAR1

01 Jan 2025·Stem Cell Reports

PKM2 is a key factor to regulate neurogenesis and cognition by controlling lactate homeostasis

Article

Author: Wu, Caixia ; Liang, Ziqi ; Zhang, Yuhong ; Jiang, Wei ; He, Pengyan ; Wang, Yuge ; Gao, Lin ; Zhang, Bingjun ; Zhu, Fan ; Tang, Changyong

Adult hippocampal neurogenesis (AHN), the process of generating new neurons from adult neural stem/progenitor cells (NSPCs), is crucial for cognitive functions and is influenced by numerous factors, including metabolic processes. Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme in glycolysis, catalyzes the production of pyruvate, which undergoes either oxidative phosphorylation or anaerobic oxidation. We observed that PKM2 is highly expressed in NSPCs, but its significance remains unclear for AHN and cognition. Using knockdown or knockout strategies, we discovered that PKM2 deficiency led to reduced AHN and impaired cognitive functions. Furthermore, we observed that knockout of PKM2 resulted in lower L-lactate levels, and supplementing L-lactate in PKM2 knockout mice improved AHN and cognitive functions. Mechanistically, L-lactate restored neurogenesis via monocarboxylate transporter 2 (MCT2), but not hydroxycarboxylic acid receptor 1. In summary, our findings demonstrate that PKM2 is essential for AHN, and lactate supplementation can restore neurogenesis in an MCT2-dependent manner.

31 Dec 2024·OncoImmunology

Lactate/GPR81 recruits regulatory T cells by modulating CX3CL1 to promote immune resistance in a highly glycolytic gastric cancer

Article

Author: Mao, Xinyuan ; Zhao, Cuiyin ; Chen, Zhian ; Su, Jin ; Hu, Yanfeng ; Wang, Weisheng ; Guo, Weihong ; Li, Guoxin ; Wang, Lingzhi

Lactate plays an important role in shaping immune tolerance in tumor microenvironment (TME) and correlates with poor prognosis in various solid tumors. Overcoming the immune resistance in an acidic TME may improve the anti-tumor immunity. Here, this study elucidated that via G-protein-coupled receptor 81 (GPR81), lactate could modulate immune tolerance in TME by recruiting regulatory T cells (Tregs) in vitro and in vivo. A high concentration of lactate was detected in cell supernatant and tissues of gastric cancer (GC), which was modulated by lactic dehydrogenase A (LDHA). GPR81 was the natural receptor of lactate and was overexpressed in different GC cell lines and samples, which correlated with poor outcomes in GC patients. Lactate/GPR81 signaling could promote the infiltration of Tregs into TME by inducing the expression of chemokine CX3CL1. GPR81 deficiency could decrease the infiltration of Tregs into TME, thereby inhibiting GC progression by weakening the inhibition of CD8⁺T cell function in a humanized mouse model. In conclusion, targeting the lactate/GPR81 signaling may potentially serve as a critical process to overcome immune resistance in highly glycolytic GC.

01 Dec 2024·The American Journal of Pathology

Endoplasmic Reticulum Stress Delays Choroid Development in the HCAR1 Knockout Mouse

Article

Author: Lachapelle, Pierre ; Zhu, Tang ; Hardy, Pierre ; Mohammad Nezhady, Mohammad A ; Hou, Xin ; Tahiri, Houda ; Modaresinejad, Monir ; Mohammad Nezhady, Mohammad Ali ; Bajon, Emmanuel ; Rivera, José Carlos ; Chemtob, Sylvain ; Rivera, José C ; Yang, Xiaojuan

The subretina, composed of the choroid and the retinal pigment epithelium (RPE), plays a critical role in proper vision. In addition to phagocytosis of photoreceptor debris, the RPE shuttles oxygen and nutrients to the neuroretina. For their own energy production, RPE cells mainly rely on lactate, a major by-product of glycolysis. Lactate, in turn, conveys most of its biological effects via the hydroxycarboxylic acid receptor 1 (HCAR1). Herein, the lactate-specific receptor, HCAR1, was found to be exclusively expressed in the RPE cells within the subretina, and Hcar1^-/- mice exhibited a substantially thinner choroidal vasculature during development. Notably, the angiogenic properties of lactate on the choroid were impacted by the absence of Hcar1. HCAR1-deficient mice exhibited elevated endoplasmic reticulum stress along with eukaryotic translation initiation factor 2α phosphorylation, a significant decrease in the global protein translation rate, and a lower proliferation rate of choroidal vasculature. Strikingly, inhibition of the integrated stress response using an inhibitor that reverses the effect of eukaryotic translation initiation factor 2α phosphorylation restored protein translation and rescued choroidal thinning. These results provide evidence that lactate signalling via HCAR1 is important for choroidal development/angiogenesis and highlight the importance of this receptor in establishing mature vision.

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HCAR1

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