Burhans Maggie S, Flowers Matthew T, Harrington Kristin R, Bond Laura M, Guo Chang-An, Anderson Rozalyn M, Ntambi James M
Departments of Nutritional Sciences, Veterans Administration Medical Center, Madison, WI 53705.
Biochemistry, Veterans Administration Medical Center, Madison, WI 53705.
J Lipid Res. 2015 Feb;56(2):304-18. doi: 10.1194/jlr.M054429. Epub 2015 Jan 2.
Hepatic steatosis is associated with detrimental metabolic phenotypes including enhanced risk for diabetes. Stearoyl-CoA desaturases (SCDs) catalyze the synthesis of MUFAs. In mice, genetic ablation of SCDs reduces hepatic de novo lipogenesis (DNL) and protects against diet-induced hepatic steatosis and adiposity. To understand the mechanism by which hepatic MUFA production influences adipose tissue stores, we created two liver-specific transgenic mouse models in the SCD1 knockout that express either human SCD5 or mouse SCD3, that synthesize oleate and palmitoleate, respectively. We demonstrate that hepatic de novo synthesized oleate, but not palmitoleate, stimulate hepatic lipid accumulation and adiposity, reversing the protective effect of the global SCD1 knockout under lipogenic conditions. Unexpectedly, the accumulation of hepatic lipid occurred without induction of the hepatic DNL program. Changes in hepatic lipid composition were reflected in plasma and in adipose tissue. Importantly, endogenously synthesized hepatic oleate was associated with suppressed DNL and fatty acid oxidation in white adipose tissue. Regression analysis revealed a strong correlation between adipose tissue lipid fuel utilization and hepatic and adipose tissue lipid storage. These data suggest an extrahepatic mechanism where endogenous hepatic oleate regulates lipid homeostasis in adipose tissues.
肝脂肪变性与有害的代谢表型相关，包括糖尿病风险增加。硬脂酰辅酶A去饱和酶（SCDs）催化单不饱和脂肪酸（MUFAs）的合成。在小鼠中，SCDs基因敲除可减少肝脏从头脂肪生成（DNL），并预防饮食诱导的肝脂肪变性和肥胖。为了了解肝脏MUFA生成影响脂肪组织储存的机制，我们在SCD1基因敲除小鼠中创建了两种肝脏特异性转基因小鼠模型，分别表达人SCD5或小鼠SCD3，它们分别合成油酸和棕榈油酸。我们证明，肝脏从头合成的油酸而非棕榈油酸会刺激肝脏脂质积累和肥胖，逆转了在脂肪生成条件下全局SCD1基因敲除的保护作用。出乎意料的是，肝脏脂质积累的发生并未诱导肝脏DNL程序。肝脏脂质组成的变化反映在血浆和脂肪组织中。重要的是，内源性合成的肝脏油酸与白色脂肪组织中DNL的抑制和脂肪酸氧化相关。回归分析显示，脂肪组织脂质燃料利用与肝脏和脂肪组织脂质储存之间存在很强的相关性。这些数据表明存在一种肝外机制，内源性肝脏油酸可调节脂肪组织中的脂质稳态。
