Division of Bariatric and Gastrointestinal Surgery, Department of Surgery, Virginia Commonwealth University, 1200 E. Broad Street, Richmond, VA, USA.
Division of Gastrointestinal Surgery, Hospital de Clínicas de Porto Alegre, 2350 Ramiro Barcelos Street, Porto Alegre, RS, Brazil.
J Gastrointest Surg. 2021 Apr;25(4):871-879. doi: 10.1007/s11605-021-04908-3. Epub 2021 Feb 8.
We interrogate effects of gastric bypass (RYGB), compared with a low-calorie diet, on bile acid (BA), liver fat, and FXR, PPARα, and targets in rats with obesity and non-alcoholic fatty liver disease (NAFLD).
Male Wistar rats received a high-fat diet (obese/NAFLD, n=24) or standard chow (lean, n=8) for 12 weeks. Obese/NAFLD rats had RYGB (n=11), sham operation pair-fed to RYGB (pair-fed sham, n=8), or sham operation (sham, n=5). Lean rats had sham operation (lean sham, n=8). Post-operatively, five RYGB rats received PPARα antagonist GW6417. Sacrifice occurred at 7 weeks. We measured weight changes, fasting total plasma BA, and liver % steatosis, triglycerides, and mRNA expression of the nuclear receptors FXR, PPARα, and their targets SHP and CPT-I.
At sacrifice, obese sham was heavier (p<0.01) than all other groups that had lost similar weight loss. Obese sham had lower BA levels and lower hepatic FXR, SHP, and CPT-I mRNA expression than lean sham (P<0.05, for all comparisons). RYGB had increased BA levels compared with obese and pair-fed sham (P<0.05, for both), while pair-fed sham had BA levels, similar to obese sham. Compared with pair-fed sham, RYGB animals had increased liver FXR and PPARα expression and signaling (P<0.05). Percentage of steatosis was lower in RYGB and lean sham, relative to obese and pair-fed sham (P<0.05, for all comparisons). PPARα inhibition after RYGB resulted in similar weight loss but higher liver triglyceride content (P=0.01) compared with RYGB alone.
RYGB led to greater liver fat loss than low-calorie diet, an effect associated to increased fasting BA levels and increased expression of modulators of liver fat oxidation, FXR, and PPARα. However, intact PPARα signaling was necessary for resolution of NAFLD after RYGB.
我们研究了胃旁路手术（RYGB）与低热量饮食相比，对胆汁酸（BA）、肝脂肪和 FXR、PPARα 以及肥胖和非酒精性脂肪性肝病（NAFLD）大鼠靶标的影响。
雄性 Wistar 大鼠接受高脂肪饮食（肥胖/NAFLD，n=24）或标准饲料（瘦，n=8）喂养 12 周。肥胖/NAFLD 大鼠接受 RYGB（n=11）、RYGB 配对喂养（配对喂养假手术，n=8）或假手术（假手术，n=5）。瘦大鼠接受假手术（瘦假手术，n=8）。手术后，5 只 RYGB 大鼠接受 PPARα 拮抗剂 GW6417 治疗。7 周后处死大鼠。我们测量体重变化、空腹总血浆 BA 以及肝脂肪含量、甘油三酯和核受体 FXR、PPARα 及其靶基因 SHP 和 CPT-I 的 mRNA 表达。
在处死时，肥胖假手术组大鼠体重高于所有其他组（p<0.01），但这些组的体重减轻程度相似。与瘦假手术组相比，肥胖假手术组 BA 水平较低，肝 FXR、SHP 和 CPT-I mRNA 表达水平较低（P<0.05，所有比较）。与肥胖和配对喂养假手术组相比，RYGB 组 BA 水平升高（P<0.05，两者均升高），而配对喂养假手术组的 BA 水平与肥胖假手术组相似。与配对喂养假手术组相比，RYGB 动物肝 FXR 和 PPARα 表达和信号增强（P<0.05）。与肥胖和配对喂养假手术组相比，RYGB 和瘦假手术组的肝脂肪变性百分比降低（P<0.05，所有比较）。与单独 RYGB 相比，RYGB 后抑制 PPARα 导致相似的体重减轻，但肝甘油三酯含量增加（P=0.01）。
RYGB 导致的肝脂肪丢失多于低热量饮食，这种作用与空腹 BA 水平升高以及肝脂肪氧化调节因子 FXR 和 PPARα 表达增加有关。然而，RYGB 后完整的 PPARα 信号传导对于 NAFLD 的恢复是必要的。
