Protection against Western diet-induced obesity and hepatic steatosis in liver fatty acid-binding protein knockout mice
Protection against Western diet-induced obesity and hepatic steatosis in liver fatty acid-binding protein knockout mice
复制标题
DOI：
10.1002/hep.21369
复制
发表时间：
2006-11-01
期刊：
影响因子：
13.5
通讯作者：
Davidson, Nicholas O.
中科院分区：
文献类型：
--
作者：
Newberry, Elizabeth P.;Xie, Yan;Davidson, Nicholas O.
肝脏脂肪酸结合蛋白(L-Fabp)调节小鼠肝脏对禁食的脂肪酸运输。在这项研究中，我们发现，与C57BL/6J对照组相比，喂食高脂西方饮食长达18周的L-Fabp(-/-)小鼠肥胖程度较低，肝脏甘油三酯积累也较少。矛盾的是，当喂食西方饮食时，对照组和L-Fabp(-/-)小鼠都表现出类似的葡萄糖耐量和胰岛素抵抗。西方饮食喂养的L-Fabp(-/-)小鼠对肥胖的保护并不是由于食物摄入量、脂肪吸收不良或热量产生的可察觉变化，尽管饮食喂养和西方饮食喂养的L-Fabp(-/-)小鼠的肠道脂肪分泌动力学明显较慢。相比之下，L-Fabp(-/-)小鼠的呼吸交换比率显著增加，表明能量底物的使用从脂肪转向碳水化合物，这一发现得到了血清乳酸增加约三倍的支持。基因芯片分析显示，在L-Fabp(-/-)小鼠中，与脂肪合成有关的基因(脂肪酸合成酶、角鲨烯环氧酶、羟甲基戊二酰辅酶A还原酶)表达增加，而与糖酵解有关的基因(葡萄糖激酶和甘油激酶)表达降低。脂肪酸合成酶在L-Fabp(-/-)小鼠的骨骼肌中的表达也增加。综上所述，L-Fabp可能作为一种代谢感受器参与调节血脂动态平衡。我们认为，通过对肝脏和肝外能量底物使用的一系列适应，L-Fabp(-/-)小鼠可以免受西方饮食诱导的肥胖和肝脏脂肪变性的影响。
Liver fatty acid-binding protein (L-Fabp) regulates murine hepatic fatty acid trafficking in response to fasting. In this study, we show that L-Fabp(-/-) mice fed a high-fat Western diet for up to 18 weeks are less obese and accumulate less hepatic triglyceride than C57BL/6J controls. Paradoxically, both control and L-Fabp(-/-) mice manifested comparable glucose intolerance and insulin resistance when fed a Western diet. Protection against obesity in Western diet-fed L-Fabp(-/-) mice was not due to discernable changes in food intake, fat malabsorption, or heat production, although intestinal lipid secretion kinetics were significantly slower in both chowfed and Western diet-fed L-Fabp(-/-) mice. By contrast, there was a significant increase in the respiratory exchange ratio in L-Fabp(-/-) mice, suggesting a shift in energy substrate use from fat to carbohydrate, findings supported by an approximately threefold increase in serum lactate. Microarray analysis revealed increased expression of genes involved in lipid synthesis (fatty acid synthase, squalene epoxidase, hydroxy-methylglutaryl coenzyme A reductase), while genes involved in glycolysis (glucokinase and glycerol kinase) were decreased in L-Fabp(-/-) mice. Fatty acid synthase expression was also increased in the skeletal muscle of L-Fabp(-/-) mice. In conclusion, L-Fabp may function as a metabolic sensor in regulating lipid homeostasis. We suggest that L-Fabp(-/-) mice are protected against Western diet-induced obesity and hepatic steatosis through a series of adaptations in both hepatic and extrahepatic energy substrate use.