胆汁结肠转流干预下胆汁酸-FXR-FGF15/19轴反馈机制对血脂异常的调节作用

Gastrointestinal bypass can influence the operation of the BA-FXR-FGF15/19 axis of bile acid (BA), which inhibits cholesterol hydroxylation and parts of lipid synthesis pathways. It may be related to the effect of serum lipid lowered by bypass, but the mechanism is unclear. We found that animals fed with cholesterol-rich diet had altered expression of lipid metabolism pathways associated with the axis in the liver, and had abnormal lipid accumulation in the body, however, gallbladder-colon anastomosis diversion could reverse this situation. We hypothesize that FGF15/19 of the axis needs to be mediated by SHP to inhibit cholesterol hydroxylation into BA, while diversion colonic blocking BA reabsorption and reducing lipid intake, upon that body fat is mobilized and the lipid synthesis associated with the axis are enhanced in liver. Eventually, due to unlimited loss of cholesterol hydroxylation, both blood lipids and body fat decreased. In this study, the gallbladder-colon anastomosis is used to construct a BA malabsorption model of Shp-/- mouse, and the agonist intervention is used to compare the content or expression level of related indicators in order to study the mechanism of action and the change of lipid metabolism pathway, as well as to validate the scientific hypothesis and verify the actual efficacy of gallbladder-colon bypass in regulating serum lipids through a hyperlipidemia rabbit model. This study will complete the mechanism of metabolic surgery to exert lipid-lowering effects, and provide more accurate theoretical basis for surgical adjuvant treatment of metabolic diseases.

消化道转流术可改变胆汁酸（BA）的BA-FXR-FGF15/19代谢轴，该轴可抑制胆固醇羟化和一部分脂质合成途径，可能与转流术降血脂作用有关，但机制不明。我们发现经高脂饮食饲养的动物，肝内与该轴相关的脂代谢途径表达改变，体内脂质异常聚集，而胆囊与结肠吻合的转流术可以逆转这一情况。我们推测：该轴FGF15/19需被SHP介导才能发挥抑制胆固醇羟化为BA的作用，但结肠转流术可阻断BA重吸收，脂摄入减少同时，该轴相关的脂合成增强并调动体脂，胆固醇羟化流失不受限，最终血脂下降、体脂含量减少。本课题以胆囊-结肠吻合法构建Shp-/-小鼠BA重吸收不良模型，借助激动剂干预，分组比较相关指标的含量或表达水平，研究该代谢轴的作用机制和对脂代谢途径的改变，验证科学假设，并通过高脂血症家兔模型验证胆囊-结肠转流术调节血脂的实际效力。本研究将完善转流术调节血脂的机制，为外科辅助治疗代谢疾病提供更确切的理论依据。

消化道转流术可改变胆汁酸代谢途径，胆汁酸相关BA-FXR-FGF15/19代谢轴可抑制胆固醇羟化和一部分脂质合成途径，可能与转流术降血脂作用有关，但机制不明。本课题通过对高脂动物模型进一步建立“胆囊-结肠”转流术的外科干预模型，研究相关脂质代谢指标，发现FGF15/19需要SHP的介导才能发挥作用，由于BA被转流后不再被重吸收进入肝脏， FGF15/19的促脂质胆酸化由于缺乏了“BA-FXR-SHP”的抑制作用而被加强。该课题为“胆囊-结肠”吻合术作为研究脂质代谢机制的外科干预手段提供全新的视角。本研究所得到相关检测结果和实验结论为外科辅助治疗代谢疾病理论补充实验依据，也证明了胆囊-结肠吻合术具备安全性和有效性，可为临床微创代谢手术新术式提供理论依据，可能带来针对治疗高脂血症及继发疾病诊疗模式面貌的改变。课题展开过程中，我们也发现胆汁酸水平的提高可诱发肝脏再生，并对相关机制进行了探究。该课题相关成果目前已以论著形式进行了发表。