Hcar2, also known as GPR109A, is a hydroxycarboxylic acid receptor. It can be modulated by endogenous ketone body β-hydroxybutyrate and exogenous niacin. HCAR2 activates Gi/o protein or β-arrestin effectors, mediating distinct pathophysiological events, and is a promising therapeutic target for inflammation-related diseases [1]. It is also involved in metabolic and immune-related pathways [3]. Genetic models, especially KO/CKO mouse models, are valuable for studying its functions.

In a 5xFAD mouse model of Alzheimer's disease, genetic inactivation of Hcar2 impairs microglial response to amyloid deposition, exacerbating amyloid burden, neuronal loss, and cognitive deficits. Conversely, activation of HCAR2 with Niaspan reduces plaque burden, neuronal dystrophy, and rescues working memory deficits, indicating its importance in the microglial neuroprotective response to amyloid pathology [2]. In a mouse model of colitis, co-administration of a Gi-biased allosteric modulator of HCAR2 (compound 9n) with orthosteric agonists enhances anti-inflammatory effects [1]. In an autochthonous animal model of colorectal cancer, β-hydroxybutyrate, acting through Hcar2, suppresses intestinal tumour growth by inducing the transcriptional regulator Hopx and inhibiting cell proliferation [4].

In conclusion, Hcar2 plays essential roles in multiple biological processes, especially in the regulation of inflammation, microglial response in Alzheimer's disease, and tumour growth in colorectal cancer. Studies using KO/CKO mouse models have provided valuable insights into its functions in these disease areas, highlighting its potential as a therapeutic target.

References:

1. Zhao, Chang, Wang, Heli, Liu, Ying, Yan, Wei, Shao, Zhenhua. 2023. Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation. In Molecular cell, 83, 3171-3187.e7. doi:10.1016/j.molcel.2023.07.030. https://pubmed.ncbi.nlm.nih.gov/37597514/

2. Moutinho, Miguel, Puntambekar, Shweta S, Tsai, Andy P, Lamb, Bruce T, Landreth, Gary E. 2022. The niacin receptor HCAR2 modulates microglial response and limits disease progression in a mouse model of Alzheimer's disease. In Science translational medicine, 14, eabl7634. doi:10.1126/scitranslmed.abl7634. https://pubmed.ncbi.nlm.nih.gov/35320002/

3. Tuteja, Sony. 2019. Activation of HCAR2 by niacin: benefits beyond lipid lowering. In Pharmacogenomics, 20, 1143-1150. doi:10.2217/pgs-2019-0092. https://pubmed.ncbi.nlm.nih.gov/31617441/

4. Dmitrieva-Posocco, Oxana, Wong, Andrea C, Lundgren, Patrick, Thaiss, Christoph A, Levy, Maayan. 2022. β-Hydroxybutyrate suppresses colorectal cancer. In Nature, 605, 160-165. doi:10.1038/s41586-022-04649-6. https://pubmed.ncbi.nlm.nih.gov/35477756/