Myronovych Andriy, Salazar-Gonzalez Rosa-Maria, Ryan Karen K, Miles Lili, Zhang Wujuan, Jha Pinky, Wang Li, Setchell Kenneth D R, Seeley Randy J, Kohli Rohit
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Obesity (Silver Spring). 2014 Nov;22(11):2301-11. doi: 10.1002/oby.20890.
Bile acids (BA) are elevated after vertical sleeve gastrectomy (VSG) and farnesoid-X-receptor (FXR) is critical to the success of murine VSG. BA downregulate hepatic lipogenesis by activating the FXR-small heterodimer partner (SHP) pathway. The role of SHP in fatty liver disease improvement after VSG was tested.
Wild type (WT), SHP liver transgenic (SHP-Tg), and SHP knockout (SHP-KO) high-fat diet (HFD) fed mice underwent either VSG or Sham surgery. Body weight, BA level and composition, steatosis, and BA metabolism gene expression were evaluated.
Obese WT mice post-VSG lost weight, reduced steatosis, decreased plasma alanine aminotransferase (ALT), had more BA absorptive ileal area, and elevated serum BA. Obese SHP-Tg mice post-VSG also lost weight and had decreased steatosis. SHP-KO mice were however resistant to steatosis despite weight gain on a HFD. Further SHP-KO mice that underwent VSG lost weight, but developed hepatic inflammation and had increased ALT.
VSG produces weight loss independent of SHP status. SHP ablation creates a proinflammatory phenotype which is exacerbated after VSG despite weight loss. These inflammatory alterations are possibly related to factors extrinsic to a direct manifestation of NASH.
垂直袖状胃切除术（VSG）后胆汁酸（BA）升高，法尼酯X受体（FXR）对小鼠VSG的成功至关重要。BA通过激活FXR-小异源二聚体伴侣（SHP）途径下调肝脏脂肪生成。本研究检测了SHP在VSG后改善脂肪肝疾病中的作用。
给野生型（WT）、SHP肝脏转基因（SHP-Tg）和SHP基因敲除（SHP-KO）的高脂饮食（HFD）喂养小鼠进行VSG或假手术。评估体重、BA水平和组成、脂肪变性以及BA代谢基因表达。
肥胖的WT小鼠VSG后体重减轻，脂肪变性减轻，血浆丙氨酸转氨酶（ALT）降低，回肠BA吸收面积增加，血清BA升高。肥胖的SHP-Tg小鼠VSG后体重也减轻，脂肪变性减少。然而，SHP-KO小鼠尽管在HFD上体重增加，但对脂肪变性有抵抗力。进一步的研究发现，接受VSG的SHP-KO小鼠体重减轻，但出现肝脏炎症且ALT升高。
VSG导致体重减轻，与SHP状态无关。SHP缺失产生一种促炎表型，尽管体重减轻，但在VSG后会加剧。这些炎症改变可能与非酒精性脂肪性肝炎直接表现的外在因素有关。
