Roux-en-Y gastric bypass induces hepatic transcriptomic signatures and plasma metabolite changes indicative of improved cholesterol homeostasis.

Humans Gastric Bypass / methods Non-alcoholic Fatty Liver Disease / genetics Transcriptome Obesity / complications Cholesterol Homeostasis Inflammation / complications Obesity, Morbid / complications
Roux-en-Y gastric bypass bile acid cholesterol liver transcriptome

Journal

Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886

Informations de publication

Date de publication:
10 2023
Historique:
received: 03 10 2022
revised: 18 04 2023
accepted: 08 05 2023
medline: 18 9 2023
pubmed: 26 5 2023
entrez: 25 5 2023
Statut: ppublish

Résumé

Roux-en-Y gastric bypass (RYGB), the most effective surgical procedure for weight loss, decreases obesity and ameliorates comorbidities, such as non-alcoholic fatty liver (NAFLD) and cardiovascular (CVD) diseases. Cholesterol is a major CVD risk factor and modulator of NAFLD development, and the liver tightly controls its metabolism. How RYGB surgery modulates systemic and hepatic cholesterol metabolism is still unclear. We studied the hepatic transcriptome of 26 patients with obesity but not diabetes before and 1 year after undergoing RYGB. In parallel, we measured quantitative changes in plasma cholesterol metabolites and bile acids (BAs). RYGB surgery improved systemic cholesterol metabolism and increased plasma total and primary BA levels. Transcriptomic analysis revealed specific alterations in the liver after RYGB, with the downregulation of a module of genes implicated in inflammation and the upregulation of three modules, one associated with BA metabolism. A dedicated analysis of hepatic genes related to cholesterol homeostasis pointed towards increased biliary cholesterol elimination after RYGB, associated with enhancement of the alternate, but not the classical, BA synthesis pathway. In parallel, alterations in the expression of genes involved in cholesterol uptake and intracellular trafficking indicate improved hepatic free cholesterol handling. Finally, RYGB decreased plasma markers of cholesterol synthesis, which correlated with an improvement in liver disease status after surgery. Our results identify specific regulatory effects of RYGB on inflammation and cholesterol metabolism. RYGB alters the hepatic transcriptome signature, likely improving liver cholesterol homeostasis. These gene regulatory effects are reflected by systemic post-surgery changes of cholesterol-related metabolites, corroborating the beneficial effects of RYGB on both hepatic and systemic cholesterol homeostasis. Roux-en-Y gastric bypass (RYGB) is a widely used bariatric surgery procedure with proven efficacy in body weight management, combatting cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). RYGB exerts many beneficial metabolic effects, by lowering plasma cholesterol and improving atherogenic dyslipidemia. Using a cohort of patients undergoing RYGB, studied before and 1 year after surgery, we analyzed how RYGB modulates hepatic and systemic cholesterol and bile acid metabolism. The results of our study provide important insights on the regulation of cholesterol homeostasis after RYGB and open avenues that could guide future monitoring and treatment strategies targeting CVD and NAFLD in obesity.

Sections du résumé

BACKGROUND & AIMS
Roux-en-Y gastric bypass (RYGB), the most effective surgical procedure for weight loss, decreases obesity and ameliorates comorbidities, such as non-alcoholic fatty liver (NAFLD) and cardiovascular (CVD) diseases. Cholesterol is a major CVD risk factor and modulator of NAFLD development, and the liver tightly controls its metabolism. How RYGB surgery modulates systemic and hepatic cholesterol metabolism is still unclear.
METHODS
We studied the hepatic transcriptome of 26 patients with obesity but not diabetes before and 1 year after undergoing RYGB. In parallel, we measured quantitative changes in plasma cholesterol metabolites and bile acids (BAs).
RESULTS
RYGB surgery improved systemic cholesterol metabolism and increased plasma total and primary BA levels. Transcriptomic analysis revealed specific alterations in the liver after RYGB, with the downregulation of a module of genes implicated in inflammation and the upregulation of three modules, one associated with BA metabolism. A dedicated analysis of hepatic genes related to cholesterol homeostasis pointed towards increased biliary cholesterol elimination after RYGB, associated with enhancement of the alternate, but not the classical, BA synthesis pathway. In parallel, alterations in the expression of genes involved in cholesterol uptake and intracellular trafficking indicate improved hepatic free cholesterol handling. Finally, RYGB decreased plasma markers of cholesterol synthesis, which correlated with an improvement in liver disease status after surgery.
CONCLUSIONS
Our results identify specific regulatory effects of RYGB on inflammation and cholesterol metabolism. RYGB alters the hepatic transcriptome signature, likely improving liver cholesterol homeostasis. These gene regulatory effects are reflected by systemic post-surgery changes of cholesterol-related metabolites, corroborating the beneficial effects of RYGB on both hepatic and systemic cholesterol homeostasis.
IMPACT AND IMPLICATIONS
Roux-en-Y gastric bypass (RYGB) is a widely used bariatric surgery procedure with proven efficacy in body weight management, combatting cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). RYGB exerts many beneficial metabolic effects, by lowering plasma cholesterol and improving atherogenic dyslipidemia. Using a cohort of patients undergoing RYGB, studied before and 1 year after surgery, we analyzed how RYGB modulates hepatic and systemic cholesterol and bile acid metabolism. The results of our study provide important insights on the regulation of cholesterol homeostasis after RYGB and open avenues that could guide future monitoring and treatment strategies targeting CVD and NAFLD in obesity.

Identifiants

DOI: 10.1016/j.jhep.2023.05.012 PMID: 37230231
pubmed: 37230231
pii: S0168-8278(23)00341-0
doi: 10.1016/j.jhep.2023.05.012
pii:
doi:

Substances chimiques

Cholesterol 97C5T2UQ7J

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

898-909

Subventions

Organisme : NIAMS NIH HHS
ID : R21 AR080233
Pays : United States

Informations de copyright

Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Auteurs

Fanny Lalloyer (F)

University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France.

Denis A Mogilenko (DA)

University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France; Department of Medicine, Department of Pathology, Microbiology and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.

Ann Verrijken (A)

Laboratory of Experimental Medicine and Pediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, 2610, Wilrijk, Antwerp, Belgium; Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, 2650, Edegem, Antwerp, Belgium.

Joel T Haas (JT)

University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France.

Antonin Lamazière (A)

Centre de Recherche Saint-Antoine, CRSA, AP-HP, Hôpital Saint Antoine, Clinical Metabolomic Department, Sorbonne Université, Inserm, F-75012, Paris, France.

Mostafa Kouach (M)

University of Lille, CHU Lille, EA 7365-GRITA-Groupe de Recherche sur les formes Injectables et les Technologies Associées, F-59000, Lille, France.

Amandine Descat (A)

University of Lille, CHU Lille, EA 7365-GRITA-Groupe de Recherche sur les formes Injectables et les Technologies Associées, F-59000, Lille, France.

Sandrine Caron (S)

University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France.

Emmanuelle Vallez (E)

University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France.

Bruno Derudas (B)

University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France.

Céline Gheeraert (C)

University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France.

Eric Baugé (E)

University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France.

Gaëtan Despres (G)

Centre de Recherche Saint-Antoine, CRSA, AP-HP, Hôpital Saint Antoine, Clinical Metabolomic Department, Sorbonne Université, Inserm, F-75012, Paris, France.

Eveline Dirinck (E)

Laboratory of Experimental Medicine and Pediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, 2610, Wilrijk, Antwerp, Belgium; Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, 2650, Edegem, Antwerp, Belgium.

Anne Tailleux (A)

University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France.

David Dombrowicz (D)

University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France.

Luc Van Gaal (L)

Laboratory of Experimental Medicine and Pediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, 2610, Wilrijk, Antwerp, Belgium; Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, 2650, Edegem, Antwerp, Belgium.

Jerôme Eeckhoute (J)

University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France.

Philippe Lefebvre (P)

University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France.

Jean-François Goossens (JF)

University of Lille, CHU Lille, EA 7365-GRITA-Groupe de Recherche sur les formes Injectables et les Technologies Associées, F-59000, Lille, France.

Sven Francque (S)

Laboratory of Experimental Medicine and Pediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, 2610, Wilrijk, Antwerp, Belgium; Department of Gastroenterology and Hepatology, Antwerp University Hospital, ERN RARE-LIVER, 2650, Edegem, Antwerp, Belgium.

Bart Staels (B)

University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France. Electronic address: bart.staels@pasteur-lille.fr.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Roux-en-Y gastric bypass induces hepatic...
questionsmedicales.fr › Procédures de chirurgie opératoire › Procédures de chirurgie digestive › Gastroentérostomie › Dérivation gastrique › Roux-en-Y gastric bypass induces hepatic...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Stéatose hépatique › Stéatose hépatique non alcoolique › Roux-en-Y gastric bypass induces hepatic...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Transcriptome › Roux-en-Y gastric bypass induces hepatic...
questionsmedicales.fr › États, signes et symptômes pathologiques › Signes et symptômes › Obésité › Roux-en-Y gastric bypass induces hepatic...
questionsmedicales.fr › Lipides › Lipides membranaires › Stérols › Cholestérol › Roux-en-Y gastric bypass induces hepatic...
questionsmedicales.fr › Phénomènes physiologiques › Homéostasie › Roux-en-Y gastric bypass induces hepatic...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Inflammation › Roux-en-Y gastric bypass induces hepatic...
questionsmedicales.fr › États, signes et symptômes pathologiques › Signes et symptômes › Obésité › Obésité morbide › Roux-en-Y gastric bypass induces hepatic...