Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2

Graff, Emily C.; Han, Fei; Wanders, Desiree; Judd, Robert L.

doi:10.1016/j.metabol.2015.10.001

Cited by 128 publications

(84 citation statements)

References 115 publications

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“…Youm et al reported that 3-hydroxybutyrate suppresses activation of the NLRP3 inflammasome in response to urate crystals, ATP and lipotoxic fatty acids, and revealed that 3-hydroxybutyrate reduces NLRP3 inflammasome-mediated interleukin (IL)-1β and IL-18 production in human monocytes [26]. The hydroxy-carboxylic acid receptor 2 (HCA2), one of the 3-hydroxybutyrate receptor, is known to be highly expressed in macrophage and also microglia in the brain [27], showing anti-inflammatory and neuroprotective actions [28, 29]. Interestingly, microglial abnormalities and dysfunction have been suggested under the pathophysiology of depression [14, 18, 30, 31].…”

Section: Discussionmentioning

confidence: 99%

Plasma Metabolites Predict Severity of Depression and Suicidal Ideation in Psychiatric Patients-A Multicenter Pilot Analysis

et al. 2016

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Evaluating the severity of depression (SOD), especially suicidal ideation (SI), is crucial in the treatment of not only patients with mood disorders but also psychiatric patients in general. SOD has been assessed on interviews such as the Hamilton Rating Scale for Depression (HAMD)-17, and/or self-administered questionnaires such as the Patient Health Questionnaire (PHQ)-9. However, these evaluation systems have relied on a person’s subjective information, which sometimes lead to difficulties in clinical settings. To resolve this limitation, a more objective SOD evaluation system is needed. Herein, we collected clinical data including HAMD-17/PHQ-9 and blood plasma of psychiatric patients from three independent clinical centers. We performed metabolome analysis of blood plasma using liquid chromatography mass spectrometry (LC-MS), and 123 metabolites were detected. Interestingly, five plasma metabolites (3-hydroxybutyrate (3HB), betaine, citrate, creatinine, and gamma-aminobutyric acid (GABA)) are commonly associated with SOD in all three independent cohort sets regardless of the presence or absence of medication and diagnostic difference. In addition, we have shown several metabolites are independently associated with sub-symptoms of depression including SI. We successfully created a classification model to discriminate depressive patients with or without SI by machine learning technique. Finally, we produced a pilot algorithm to predict a grade of SI with citrate and kynurenine. The above metabolites may have strongly been associated with the underlying novel biological pathophysiology of SOD. We should explore the biological impact of these metabolites on depressive symptoms by utilizing a cross species study model with human and rodents. The present multicenter pilot study offers a potential utility for measuring blood metabolites as a novel objective tool for not only assessing SOD but also evaluating therapeutic efficacy in clinical practice. In addition, modification of these metabolites by diet and/or medications may be a novel therapeutic target for depression. To clarify these aspects, clinical trials measuring metabolites before/after interventions should be conducted. Larger cohort studies including non-clinical subjects are also warranted to clarify our pilot findings.

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Section: Discussionmentioning

confidence: 99%

Plasma Metabolites Predict Severity of Depression and Suicidal Ideation in Psychiatric Patients-A Multicenter Pilot Analysis

et al. 2016

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“…Anti-inflammatory roles of GPR109A ligands in atherosclerosis, obesity, inflammatory bowel disease, neurological disease, and cancer have been reviewed (Graff et al, 2016). GPR109A expression is augmented in RPE cells of diabetic models, human diabetic patients (Gambhir et al, 2012), and in microglia during neurodegeneration (Fu et al, 2014).…”

Section: Anti- and Pro-inflammatory Responses To Ketone Bodiesmentioning

confidence: 99%

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

2017

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Ketone body metabolism is a central node in physiological homeostasis. In this review, we discuss how ketones serve discrete fine-tuning metabolic roles that optimize organ and organism performance in varying nutrient states, and protect from inflammation and injury in multiple organ systems. Traditionally viewed as metabolic substrates enlisted only in carbohydrate restriction, recent observations underscore the importance of ketone bodies as vital metabolic and signaling mediators when carbohydrates are abundant. Complementing a repertoire of known therapeutic options for diseases of the nervous system, prospective roles for ketone bodies in cancer have arisen, as have intriguing protective roles in heart and liver, opening therapeutic options in obesity-related and cardiovascular disease. Controversies in ketone metabolism and signaling are discussed to reconcile classical dogma with contemporary observations.

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“…The recent discovery that BHB acts as an endogenous ligand for hydroxycarboxylic acid receptor 2 (HCAR2) has expanded the role of BHB beyond that of a mere energy substrate . An experimental ischemic model showed that the activation of HCAR2 reduced the infarct volume, and this beneficial effect was lost in animals with the genetic deletion of HCAR2 .…”

Section: Fatty Acid and Kbmentioning

confidence: 99%

Metabolic compartmentalization between astroglia and neurons in physiological and pathophysiological conditions of the neurovascular unit

Takahashi

2020

Neuropathology

160

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Astroglia or astrocytes, the most abundant cells in the brain, are interposed between neuronal synapses and microvasculature in the brain gray matter. They play a pivotal role in brain metabolism as well as in the regulation of cerebral blood flow, taking advantage of their unique anatomical location. In particular, the astroglial cellular metabolic compartment exerts supportive roles in dedicating neurons to the generation of action potentials and protects them against oxidative stress associated with their high energy consumption. An impairment of normal astroglial function, therefore, can lead to numerous neurological disorders including stroke, neurodegenerative diseases, and neuroimmunological diseases, in which metabolic derangements accelerate neuronal damage. The neurovascular unit (NVU), the major components of which include neurons, microvessels, and astroglia, is a conceptual framework that was originally used to better understand the pathophysiology of cerebral ischemia. At present, the NVU is a tool for understanding normal brain physiology as well as the pathophysiology of numerous neurological disorders. The metabolic responses of astroglia in the NVU can be either protective or deleterious. This review focuses on three major metabolic compartments: (i) glucose and lactate; (ii) fatty acid and ketone bodies; and (iii) D‐ and L‐serine. Both the beneficial and the detrimental roles of compartmentalization between neurons and astroglia will be discussed. A better understanding of the astroglial metabolic response in the NVU is expected to lead to the development of novel therapeutic strategies for diverse neurological diseases.

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Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2

Cited by 128 publications

References 115 publications

Plasma Metabolites Predict Severity of Depression and Suicidal Ideation in Psychiatric Patients-A Multicenter Pilot Analysis

Plasma Metabolites Predict Severity of Depression and Suicidal Ideation in Psychiatric Patients-A Multicenter Pilot Analysis

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

Metabolic compartmentalization between astroglia and neurons in physiological and pathophysiological conditions of the neurovascular unit

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