Identification of novel GPR81 agonist lead series for target biology evaluation

Davidsson, Öjvind; Nilsson, Kristina; Brånalt, Jonas; Andersson, Terese; Berggren, Kristina; Chen, Yantao; Fjellström, Ola; Gradén, Henrik; Gustafsson, Linda; Jansen, Frank; Johannesson, Petra; Ohlsson, Bengt; Tyrchan, Christian; Wellner, Annika; Wellner, Eric; Ölwegård-Halvarsson, Maria

doi:10.1016/j.bmcl.2020.126953

Cited by 5 publications

(3 citation statements)

References 33 publications

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“…HCAR1 can bind to lactate to play a neuroprotective role, inducing VEGFA secretion and promoting cerebrovascular production, which plays a significant role in the repair of brain injury ( 8 ). By establishing the middle cerebral artery occlusion model, HCAR1 expression could be significantly up-regulated in both hippocampus and cerebral cortex, which could effectively improve the cerebral infarction area of middle cerebral artery occlusion model and improve the neuronal cell survival rate after the intervention of D-lactate and 3,5-DHBA ( 9 ). With the large number of brain fibroblasts-like cells, their functional status changes and their morphological structure changes ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

Exercise Regulates the Lactate Receptor HCAR1 and ERK1/2-PI3K/Akt Pathways to Promote Cerebral Angiogenesis

Zhang¹,

Wu²,

Zhan³

et al. 2022

ijph

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Background: We aimed to explore the ole and mechanism of lactate receptor (HCAR1) in the angiogenesis of leptomeningeal fibroblast-like cells. Methods: Human brain fibroblast-like cells were selected and some cells were deactivated, analyzed and compared with HCAR1 mRNA and protein expressions in deactivated/normal cells. HCAR1-/- mice and wild type (WT) mice were selected and divided into WT, WT exercise, HCAE1 KO and HCAE1 KO exercise groups, with 10 mice for each group. HCAR1mRNA and expression levels of proteins in fibroblast-like cells, mRNA and expression levels of proteins in Collagen IV, phosphatidylinositol trihydroxykinase (PI3K), serine threonine kinase (AKT) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) in hippocampus were compared, and the microvessel density (MVD) and diameter were calculated. Results: mRNA and expression levels of proteins in Collagen IV, PI3K, AKT, ERK1/2 and MVD in hippocampus were significantly higher in the WT exercise group than those in the WT group, microvessel diameter was significantly lower than that in the WT group (P<0.05). mRNA and expression levels of proteins in Collagen IV, PI3K, AKT, ERK1/2 and MVD in hippocampus in the HCAR1 KO and HCAR1 KO exercise groups were significantly lower than those in the WT group, microvessel diameter was higher than that in the WT group (P<0.05). Compared with the HCAR1 KO exercise group, the changes of mRNA in Collagen IV, PI3K, AKT, ERK1/2 and microvascular were not significant. Conclusion: Exercise can promote cerebral angiogenesis through the activation of the lactate receptor HCAR1 and the ERK1/2-PI3K/Akt signaling pathways.

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Section: Introductionmentioning

confidence: 99%

Exercise Regulates the Lactate Receptor HCAR1 and ERK1/2-PI3K/Akt Pathways to Promote Cerebral Angiogenesis

Zhang¹,

Wu²,

Zhan³

et al. 2022

ijph

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“…GPR81 is a member of the hydroxyl-carboxylic acid receptor family. GPR81 is highly expressed in adipose tissue but also found in kidney, skeletal muscle, and liver ( 26 , 89 ). Lactate is an endogenous ligand for GPR81.…”

Section: Gpcr Signaling Pathways In Metabolismmentioning

confidence: 99%

Metabolic Functions of G Protein-Coupled Receptors and β-Arrestin-Mediated Signaling Pathways in the Pathophysiology of Type 2 Diabetes and Obesity

Souza

Sun

2021

Front. Endocrinol.

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Seven transmembrane receptors (7TMRs), often termed G protein-coupled receptors (GPCRs), are the most common target of therapeutic drugs used today. Many studies suggest that distinct members of the GPCR superfamily represent potential targets for the treatment of various metabolic disorders including obesity and type 2 diabetes (T2D). GPCRs typically activate different classes of heterotrimeric G proteins, which can be subgrouped into four major functional types: Gαs, Gαi, Gαq/11, and G12/13, in response to agonist binding. Accumulating evidence suggests that GPCRs can also initiate β-arrestin-dependent, G protein-independent signaling. Thus, the physiological outcome of activating a certain GPCR in a particular tissue may also be modulated by β-arrestin-dependent, but G protein-independent signaling pathways. In this review, we will focus on the role of G protein- and β-arrestin-dependent signaling pathways in the development of obesity and T2D-related metabolic disorders.

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“…Lactate signaling through GPR81, if present during Mtb infection, may have dual roles during infection, and future research to explore these hypotheses is warranted. Multiple synthetic agonists of GPR81 have been identified, some of which are commercially available, including 3-chloro-5-hydroxybenzoic acid and 3,5 dihydroxybenzoic acid (DHBA) (Dvorak et al, 2012;Liu et al, 2012;Sakurai et al, 2014;Geyer et al, 2015;Davidsson et al, 2020). These agonists have been investigated as alternative dyslipidemic agents to niacin, which signals through GPR109A and causes an undesired flushing reaction due to prostaglandin activation of Langerhans cells, but have yet to be actively explored as therapeutics for infectious disease applications (Dvorak et al, 2012;Liu et al, 2012;Sakurai et al, 2014).…”

Section: The Importance Of Lactate As a Signaling Molecule Introduction To Gpr81mentioning

confidence: 99%

Lactate Metabolism and Signaling in Tuberculosis and Cancer: A Comparative Review

Kiran

Basaraba

2021

Front. Cell. Infect. Microbiol.

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Infection with Mycobacterium tuberculosis (Mtb) leading to tuberculosis (TB) disease continues to be a major global health challenge. Critical barriers, including but not limited to the development of multi-drug resistance, lack of diagnostic assays that detect patients with latent TB, an effective vaccine that prevents Mtb infection, and infectious and non-infectious comorbidities that complicate active TB, continue to hinder progress toward a TB cure. To complement the ongoing development of new antimicrobial drugs, investigators in the field are exploring the value of host-directed therapies (HDTs). This therapeutic strategy targets the host, rather than Mtb, and is intended to augment host responses to infection such that the host is better equipped to prevent or clear infection and resolve chronic inflammation. Metabolic pathways of immune cells have been identified as promising HDT targets as more metabolites and metabolic pathways have shown to play a role in TB pathogenesis and disease progression. Specifically, this review highlights the potential role of lactate as both an immunomodulatory metabolite and a potentially important signaling molecule during the host response to Mtb infection. While long thought to be an inert end product of primarily glucose metabolism, the cancer research field has discovered the importance of lactate in carcinogenesis and resistance to chemotherapeutic drug treatment. Herein, we discuss similarities between the TB granuloma and tumor microenvironments in the context of lactate metabolism and identify key metabolic and signaling pathways that have been shown to play a role in tumor progression but have yet to be explored within the context of TB. Ultimately, lactate metabolism and signaling could be viable HDT targets for TB; however, critical additional research is needed to better understand the role of lactate at the host-pathogen interface during Mtb infection before adopting this HDT strategy.

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Identification of novel GPR81 agonist lead series for target biology evaluation

Cited by 5 publications

References 33 publications

Exercise Regulates the Lactate Receptor HCAR1 and ERK1/2-PI3K/Akt Pathways to Promote Cerebral Angiogenesis

Exercise Regulates the Lactate Receptor HCAR1 and ERK1/2-PI3K/Akt Pathways to Promote Cerebral Angiogenesis

Metabolic Functions of G Protein-Coupled Receptors and β-Arrestin-Mediated Signaling Pathways in the Pathophysiology of Type 2 Diabetes and Obesity

Lactate Metabolism and Signaling in Tuberculosis and Cancer: A Comparative Review

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