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Defective Bile Acid Signaling Promotes Vascular Dysfunction, Supporting a Role for G-Protein Bile Acid Receptor 1/Farnesoid X Receptor Agonism and Statins in the Treatment of Nonalcoholic Fatty Liver Disease

Journal of the American Heart Association, 2023-12, Vol.12 (23), p.e031241-e031241 [Peer Reviewed Journal]

2023 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. ;ISSN: 2047-9980 ;EISSN: 2047-9980 ;DOI: 10.1161/JAHA.123.031241 ;PMID: 37996988

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Title:
Defective Bile Acid Signaling Promotes Vascular Dysfunction, Supporting a Role for G-Protein Bile Acid Receptor 1/Farnesoid X Receptor Agonism and Statins in the Treatment of Nonalcoholic Fatty Liver Disease
Author: Marchianò, Silvia ; Biagioli, Michele ; Bordoni, Martina ; Morretta, Elva ; Di Giorgio, Cristina ; Vellecco, Valentina ; Roselli, Rosalinda ; Bellini, Rachele ; Massa, Carmen ; Cari, Luigi ; Urbani, Ginevra ; Ricci, Patrizia ; Monti, Maria Chiara ; Giordano, Antonino ; Brancaleone, Vincenzo ; Bucci, Mariarosaria ; Zampella, Angela ; Distrutti, Eleonora ; Cieri, Enrico ; Cirino, Giuseppe ; Fiorucci, Stefano
Subjects: Animals ; Atorvastatin - pharmacology ; Atorvastatin - therapeutic use ; bile acid signaling ; Bile Acids and Salts - metabolism ; cardiovascular diseases ; Dysbiosis - complications ; Dysbiosis - metabolism ; farnesoid X receptor ; GTP-Binding Proteins - metabolism ; G‐protein bile acid receptor 1 ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use ; Liver - metabolism ; Mice ; Non-alcoholic Fatty Liver Disease - drug therapy ; Non-alcoholic Fatty Liver Disease - genetics ; nonalcoholic steatohepatitis ; Original Research ; Receptors, G-Protein-Coupled - metabolism
Is Part Of: Journal of the American Heart Association, 2023-12, Vol.12 (23), p.e031241-e031241
Description: Patients with nonalcoholic fatty liver disease are at increased risk to develop atherosclerotic cardiovascular diseases. FXR and GPBAR1 are 2 bile acid-activated receptors exploited in the treatment of nonalcoholic fatty liver disease: whether dual GPBAR1/FXR agonists synergize with statins in the treatment of the liver and cardiovascular components of nonalcoholic fatty liver disease is unknown. Investigations of human aortic samples obtained from patients who underwent surgery for aortic aneurysms and , , and dual mice demonstrated that GPBAR1 and FXR are expressed in the aortic wall and regulate endothelial cell/macrophage interactions. The expression of GPBAR1 in the human endothelium correlated with the expression of inflammatory biomarkers. Mice lacking and / display hypotension and aortic inflammation, along with altered intestinal permeability that deteriorates with age, and severe dysbiosis, along with dysregulated bile acid synthesis. Vasomotor activities of aortic rings were altered by and gene ablation. In apolipoprotein E and wild-type mice, BAR502, a dual GPBAR1/FXR agonist, alone or in combination with atorvastatin, reduced cholesterol and low-density lipoprotein plasma levels, mitigated the development of liver steatosis and aortic plaque formation, and shifted the polarization of circulating leukocytes toward an anti-inflammatory phenotype. BAR502/atorvastatin reversed intestinal dysbiosis and dysregulated bile acid synthesis, promoting a shift of bile acid pool composition toward FXR antagonists and GPBAR1 agonists. FXR and GPBAR1 maintain intestinal, liver, and cardiovascular homeostasis, and their therapeutic targeting with a dual GPBAR1/FXR ligand and atorvastatin holds potential in the treatment of liver and cardiovascular components of nonalcoholic fatty liver disease.
Publisher: England: John Wiley and Sons Inc
Language: English
Identifier: ISSN: 2047-9980
EISSN: 2047-9980
DOI: 10.1161/JAHA.123.031241
PMID: 37996988
Source: Open Access: PubMed Central
Geneva Foundation Free Medical Journals at publisher websites
Directory of Open Access Journals*
MEDLINE
Wiley Online Library Open Access
ROAD: Directory of Open Access Scholarly Resources

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Defective Bile Acid Signaling Promotes Vascular Dysfunction, Supporting a Role for G-Protein Bile Acid Receptor 1/Farnesoid X Receptor Agonism and Statins in the Treatment of Nonalcoholic Fatty Liver Disease

2023 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. ;ISSN: 2047-9980 ;EISSN: 2047-9980 ;DOI: 10.1161/JAHA.123.031241 ;PMID: 37996988

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