The roles of GRP81 as a metabolic sensor and inflammatory mediator

Hu, Jingyun; Cai, Ming; Liu, Yuran; Liu, Beibei; Xue, Xiangli; Ji, Rui-Fang; Bian, Xuepeng; Lou, Shujie

doi:10.1002/jcp.29739

Cited by 33 publications

(23 citation statements)

References 92 publications

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“…Recently, studies signify that lactate is not merely an energy resource of neurons, but plays as a molecule to regulate activities of neural cells [31]. As a signaling regulator, lactate can bind to its receptor, GPR81, which can activate PI3K/Akt, ERK1/2 and NLRP3/NF-κB pathways [23]. Also, lactate can signal by being transported into neurons through MCTs, which further modulates redox-dependent and energy-dependent mechanism [32].…”

Section: Discussionmentioning

confidence: 99%

“…Actually, lactate is not merely an energy resource, but also recognized as a signaling molecule [22]. Lactate can bind to its receptor, G protein-coupled receptor 81 (GPR81), which activates several downstreams, including phosphatidylinositol 3 kinase /protein kinase B (PI3K/Akt), extracellular regulated protein kinases (ERK1/2) pathway, Nod-like receptor family pyrin domain-containing 3/nuclear factor-κB (NLRP3/NF-κB) in ammatory signaling pathway and so on [23].…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Lactate-GPR81-PI3K/Akt Pathway May Exacerbate Aβ Aggregation in 3-Month-Old APP/PS1 Mice

Zhang¹,

Wang²,

Chen³

et al. 2021

Preprint

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Lactate is not only an energy metabolite for neurons, but also serves as a molecule regulator affecting neuronal activity through its receptor, G protein-coupled receptor 81 (GPR81). This receptor can trigger cellular signaling pathways, such as phosphatidylinositol 3 kinase /protein kinase B (PI3K/Akt) pathway. Particularly, lactate deficit and inhibition of PI3K/Akt pathway were observed to be related with early synaptic dysfunction in Alzheimer’s disease (AD). In addition, amyloid beta (Aβ) is toxic to neurons, while in vitro lactate administration of neurons can resist against this toxicity. Hence, this work focuses on the effect of lactate deficiency on Aβ production, suggesting that lactate decrease can inhibit GPR81-PI3K/Akt pathway, and then reduce deoxyribonucleic acid methyltransferase 1 (DNMT1) expression, further resulting in increase of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and Aβ production. Based on the analysis of results, this study primarily proves that lactate reduction suppresses its downstream GPR81-PI3K/Akt pathway, which decreases the expression of DNMT1 through regulating cyclic-adenosine-monophosphate response element-binding protein (CREB)/P300. Then, it is proved that DNMT1 reduction can lead to the increase of BACE1 and Aβ accumulation in AD. At last, in vitro experiment recognizes that lactate directly activates GPR81-PI3K/Akt pathway. Thus, this study provides a novel insight in Aβ production in relation with lactate deficit at early stage of AD. Particularly, it is suggested that extra addition of lactate might be protective for neurons targeting Aβ clearance in early treatment of AD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of Lactate-GPR81-PI3K/Akt Pathway May Exacerbate Aβ Aggregation in 3-Month-Old APP/PS1 Mice

Zhang¹,

Wang²,

Chen³

et al. 2021

Preprint

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“…Lactate binding to HCA1 can also signal through a noncanonical, cAMP/PKA-independent pathway with arrestin beta 2 (ARRB2) as an adaptor protein, leading to the inhibition of toll-like receptor-4 (TLR-4)- and nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated induction of proinflammatory mediators such as interleukin (IL)-1β and IL-18 [ 47 , 48 , 53 ].…”

Section: Lactate Receptormentioning

confidence: 99%

Lactate: a multifunctional signaling molecule

Lee

2021

Yeungnam Univ J Med

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Since its discovery in 1780, lactate has long been misunderstood as a waste by-product of anaerobic glycolysis with multiple deleterious effects. Owing to the lactate shuttle concept introduced in the early 1980s, a paradigm shift began to occur. Increasing evidence indicates that lactate is a coordinator of whole-body metabolism. Lactate is not only a readily accessible fuel that is shuttled throughout the body but also a metabolic buffer that bridges glycolysis and oxidative phosphorylation between cells and intracellular compartments. Lactate also acts as a multifunctional signaling molecule through receptors expressed in various cells and tissues, resulting in diverse biological consequences including decreased lipolysis, immune regulation, anti-inflammation, wound healing, and enhanced exercise performance in association with the gut microbiome. Furthermore, lactate contributes to epigenetic gene regulation by lactylating lysine residues of histones, accounting for its key role in immune modulation and maintenance of homeostasis.

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“…TNF-α and IL-1β, secreted by macrophages, increase GPR81 expression [ 133 , 134 ]. Selective activation of GPR81 may serve as a novel treatment target against endothelial inflammation and the development of atherosclerosis induced by oscillatory shear stress [ 135 , 136 ]. Blood lactate is associated with carotid atherosclerosis and is related to insulin resistance [ 137 ].…”

Section: Lipid Metabolitesmentioning

confidence: 99%

Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases

Strassheim

Sullivan

Irwin

et al. 2021

Cells

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G protein-coupled receptors (GPCRs) have originally been described as a family of receptors activated by hormones, neurotransmitters, and other mediators. However, in recent years GPCRs have shown to bind endogenous metabolites, which serve functions other than as signaling mediators. These receptors respond to fatty acids, mono- and disaccharides, amino acids, or various intermediates and products of metabolism, including ketone bodies, lactate, succinate, or bile acids. Given that many of these metabolic processes are dysregulated under pathological conditions, including diabetes, dyslipidemia, and obesity, receptors of endogenous metabolites have also been recognized as potential drug targets to prevent and/or treat metabolic and cardiovascular diseases. This review describes G protein-coupled receptors activated by endogenous metabolites and summarizes their physiological, pathophysiological, and potential pharmacological roles.

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The roles of GRP81 as a metabolic sensor and inflammatory mediator

Cited by 33 publications

References 92 publications

Inhibition of Lactate-GPR81-PI3K/Akt Pathway May Exacerbate Aβ Aggregation in 3-Month-Old APP/PS1 Mice

Inhibition of Lactate-GPR81-PI3K/Akt Pathway May Exacerbate Aβ Aggregation in 3-Month-Old APP/PS1 Mice

Lactate: a multifunctional signaling molecule

Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases

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