Nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP) are important regulators of bile acid, lipid, and glucose homeostasis. Here, we show that global Fxr ^–/– Shp^–/– double knockout (DKO) mice are refractory to weight gain, glucose intolerance, and hepatic steatosis when challenged with high-fat diet. DKO mice display an inherently increased capacity to burn fat and suppress de novo hepatic lipid synthesis. Moreover, DKO mice were also very active and that correlated well with the observed increase in phosphoenolpyruvate carboxykinase expression, type IA fibers, and mitochondrial function in skeletal muscle. Mechanistically, we demonstrate that liver-specific Shp deletion protects against fatty liver development by suppressing expression of peroxisome proliferator-activated receptor gamma 2 and lipid-droplet protein fat-specific protein 27 beta. Conclusion: These data suggest that Fxr and Shp inactivation may be beneficial to combat diet-induced obesity and uncover that hepatic SHP is necessary to promote fatty liver disease. (Hepatology 2017;66:1854–1865)

中文翻译：

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小异二聚体伴侣缺失可防止肝脂肪变性，当与法呢类X受体结合使用时，可预防小鼠的2型糖尿病

核受体法呢类X受体（FXR）和小异二聚体伴侣（SHP）是胆汁酸，脂质和葡萄糖体内稳态的重要调节剂。在这里，我们显示，全球FXR ^{- / -} SHP ^{- / -}当与高脂肪食物的挑战双敲除（DKO）小鼠中有顽固性体重增加，葡萄糖耐受不良，和肝脂肪变性。DKO小鼠具有天生的燃烧脂肪和抑制从头肝脂质合成的能力。此外，DKO小鼠也非常活跃，并且与所观察到的磷酸烯醇丙酮酸羧化激酶表达，IA型纤维和骨骼肌线粒体功能增加密切相关。从机理上讲，我们证明了肝脏特异性Shp缺失通过抑制过氧化物酶体增殖物激活的受体γ2和脂滴蛋白脂肪特异性蛋白27β的表达来保护脂肪肝的发展。结论：这些数据表明，FXR和SHP失活可能是作战饮食引起的肥胖，揭示肝SHP是必要的，以促进脂肪肝疾病有益。（肝病学， 2017年； 66：1854–1865）