Journal of Hepatology ( IF 26.8 ) Pub Date : 2023-05-23 , DOI: 10.1016/j.jhep.2023.05.012 Fanny Lalloyer 1 , Denis A Mogilenko 2 , Ann Verrijken 3 , Joel T Haas 1 , Antonin Lamazière 4 , Mostafa Kouach 5 , Amandine Descat 5 , Sandrine Caron 1 , Emmanuelle Vallez 1 , Bruno Derudas 1 , Céline Gheeraert 1 , Eric Baugé 1 , Gaëtan Despres 4 , Eveline Dirinck 3 , Anne Tailleux 1 , David Dombrowicz 1 , Luc Van Gaal 3 , Jerôme Eeckhoute 1 , Philippe Lefebvre 1 , Jean-François Goossens 5 , Sven Francque 6 , Bart Staels 1
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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.
中文翻译：
Roux-en-Y胃绕道术诱导肝脏转录组特征和血浆代谢物变化，表明胆固醇稳态得到改善
背景与目标
Roux-en-Y 胃绕道手术 (RYGB) 是最有效的减肥手术，可减少肥胖并改善合并症，例如非酒精性脂肪肝 (NAFLD) 和心血管 (CVD) 疾病。胆固醇是主要的 CVD 危险因素和 NAFLD 发展的调节剂，肝脏严格控制其代谢。RYGB 手术如何调节全身和肝脏胆固醇代谢尚不清楚。
方法
我们研究了26 名肥胖但未患糖尿病的患者在接受 RYGB 之前和之后 1 年的肝脏转录组。与此同时，我们测量了血浆胆固醇代谢物和胆汁酸（BA）的定量变化。
结果
RYGB 手术改善了全身胆固醇代谢并提高了血浆总 BA 和初级 BA 水平。转录组分析揭示了 RYGB 后肝脏发生了特定的变化，与炎症有关的一个基因模块下调，而三个模块上调，其中一个与BA 代谢相关。对与胆固醇稳态相关的肝脏基因的专门分析表明，RYGB 后胆汁胆固醇消除增加，与替代的 BA 合成途径的增强相关，但与经典的 BA 合成途径无关。与此同时，参与胆固醇摄取和细胞内运输的基因表达的改变表明肝脏游离胆固醇处理能力的改善。最后，RYGB 降低了胆固醇合成的血浆标志物，这与术后肝病状况的改善相关。
结论
我们的结果确定了 RYGB 对炎症和胆固醇代谢的具体调节作用。RYGB 改变肝脏转录组特征，可能改善肝脏胆固醇稳态。这些基因调控作用通过胆固醇相关代谢物的系统性术后变化得到反映，证实了 RYGB 对肝脏和全身胆固醇稳态的有益作用。
影响和影响
Roux-en-Y 胃绕道手术 (RYGB) 是一种广泛使用的减肥手术，在体重管理、对抗心血管疾病 (CVD) 和非酒精性脂肪肝 (NAFLD) 方面已被证明有效。RYGB 通过降低血浆胆固醇和改善动脉粥样硬化性血脂异常，发挥许多有益的代谢作用。通过对一组接受 RYGB 的患者进行术前和术后 1 年的研究，我们分析了 RYGB 如何调节肝脏和全身胆固醇和胆汁酸代谢。我们的研究结果为 RYGB 后胆固醇稳态的调节提供了重要见解，并开辟了指导未来针对肥胖 CVD 和 NAFLD 监测和治疗策略的途径。
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