G protein-coupled receptors: Key molecules in metabolic associated fatty liver disease development

López-Méndez, Iván; Méndez-Maldonado, Karla; Manzo-Francisco, Luis A.; Juárez-Hernández, Eva; Uribe, Misael; Barbero-Becerra, Varenka J.

doi:10.1016/j.nutres.2020.12.019

Cited by 6 publications

(6 citation statements)

References 72 publications

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“…Study has shown that SCFA activate GPR41 and GPR43 on intestinal epithelial cells, leading to inflammatory responses in mice. 54 Moreover, GPR41 is increased in the lean nonoverweight-obese/MAFLD patients, 55 suggesting that fatty liver disease is associated with characteristic inflammation profile. And thus, decreased expression of GPR41 and GPR43 is likely to be associated with decreased inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

Astragalus mongholicus polysaccharides ameliorate hepatic lipid accumulation and inflammation as well as modulate gut microbiota in NAFLD rats

et al. 2022

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Section: Discussionmentioning

confidence: 99%

Astragalus mongholicus polysaccharides ameliorate hepatic lipid accumulation and inflammation as well as modulate gut microbiota in NAFLD rats

et al. 2022

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“…SCFAs such as BUT bind to and activate G-protein-coupled receptors FFAR2 and FFAR3 with different selectivities ( Brown et al, 2003 ; Bindels et al, 2013 ). FFAR2 and FFAR3 are expressed in adipose tissue and immune cells ( Brown et al, 2003 ), as well as in hepatocytes and the intestinal epithelium ( Chambers et al, 2015 ; Lopez-Mendez et al, 2021 ). Their expression in vascular EC is still a matter of debate and, consequently, little is known if and how FFAR2/3 functions in vascular EC.…”

Section: Discussionmentioning

confidence: 99%

The short-chain fatty acid butyrate exerts a specific effect on VE-cadherin phosphorylation and alters the integrity of aortic endothelial cells

Guo

Terhorst

Stammer

et al. 2023

Front. Cell Dev. Biol.

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Short-chain fatty acids (SCFAs) like butyrate (BUT) largely influence vascular integrity and are closely associated with the onset and progression of cardiovascular diseases. However, their impact on vascular endothelial cadherin (VEC), a major vascular adhesion and signaling molecule, is largely unknown. Here, we explored the effect of the SCFA BUT on the phosphorylation of specific tyrosine residues of VEC (Y731, Y685, and Y658), which are reported to be critical for VEC regulation and vascular integrity. Moreover, we shed light on the signaling pathway engaged by BUT to affect the phosphorylation of VEC. Thereby, we used phospho-specific antibodies to evaluate the phosphorylation of VEC in response to the SCFA sodium butyrate in human aortic endothelial cells (HAOECs) and performed dextran assays to analyze the permeability of the EC monolayer. The role of c-Src and SCFA receptors FFAR2 and FFAR3 in the induction of VEC phosphorylation was analyzed using inhibitors and antagonists for c-Src family kinases and FFAR2/3, respectively, as well as by RNAi-mediated knockdown. Localization of VEC in response to BUT was assessed by fluorescence microscopy. BUT treatment of HAOEC resulted in the specific phosphorylation of Y731 at VEC with minor effects on Y685 and Y658. Thereby, BUT engages FFAR3, FFAR2, and c-Src kinase to induce phosphorylation of VEC. VEC phosphorylation correlated with enhanced endothelial permeability and c-Src-dependent remodeling of junctional VEC. Our data suggest that BUT, an SCFA and gut microbiota-derived metabolite, impacts vascular integrity by targeting VEC phosphorylation with potential impact on the pathophysiology and therapy of vascular diseases.

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“…GPCRs are the largest family of surface receptors widely expressed in the body and play a vital role in multiple biological processes [ 43 , 44 , 45 , 46 , 47 ]. ADRβ 3 is one of the members of this family and is highly expressed in adipose tissue.…”

Section: Discussionmentioning

confidence: 99%

Functional Characterization of the Obesity-Linked Variant of the β3-Adrenergic Receptor

Haji

Mahri

Aloraij

et al. 2021

IJMS

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Adrenergic receptor β3 (ADRβ3) is a member of the rhodopsin-like G protein-coupled receptor family. The binding of the ligand to ADRβ3 activates adenylate cyclase and increases cAMP in the cells. ADRβ3 is highly expressed in white and brown adipocytes and controls key regulatory pathways of lipid metabolism. Trp64Arg (W64R) polymorphism in the ADRβ3 is associated with the early development of type 2 diabetes mellitus, lower resting metabolic rate, abdominal obesity, and insulin resistance. It is unclear how the substitution of W64R affects the functioning of ADRβ3. This study was initiated to functionally characterize this obesity-linked variant of ADRβ3. We evaluated in detail the expression, subcellular distribution, and post-activation behavior of the WT and W64R ADRβ3 using single cell quantitative fluorescence microscopy. When expressed in HEK 293 cells, ADRβ3 shows a typical distribution displayed by other GPCRs with a predominant localization at the cell surface. Unlike adrenergic receptor β2 (ADRβ2), agonist-induced desensitization of ADRβ3 does not involve loss of cell surface expression. WT and W64R variant of ADRβ3 displayed comparable biochemical properties, and there was no significant impact of the substitution of tryptophan with arginine on the expression, cellular distribution, signaling, and post-activation behavior of ADRβ3. The obesity-linked W64R variant of ADRβ3 is indistinguishable from the WT ADRβ3 in terms of expression, cellular distribution, signaling, and post-activation behavior.

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G protein-coupled receptors: Key molecules in metabolic associated fatty liver disease development

Cited by 6 publications

References 72 publications

Astragalus mongholicus polysaccharides ameliorate hepatic lipid accumulation and inflammation as well as modulate gut microbiota in NAFLD rats

Astragalus mongholicus polysaccharides ameliorate hepatic lipid accumulation and inflammation as well as modulate gut microbiota in NAFLD rats

The short-chain fatty acid butyrate exerts a specific effect on VE-cadherin phosphorylation and alters the integrity of aortic endothelial cells

Functional Characterization of the Obesity-Linked Variant of the β3-Adrenergic Receptor

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