Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease.
Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease.
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DOI：
10.1007/s10620-016-4054-0
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发表时间：
2016-05
影响因子：
3.1
通讯作者：
Kahn CR
中科院分区：
文献类型：
--
作者：
Softic S;Cohen DE;Kahn CR
非酒精性脂肪性肝病(NAFLD)是代谢综合征的肝脏表现。过量食用高脂饮食(HFD)和增加含糖饮料的摄入量是NAFLD发生的主要危险因素。如今，最常消费的糖是高果糖玉米糖浆。肝脂可能来源于饮食摄入、血浆游离脂肪酸(FFA)的酯化或肝脏的新生脂肪生成(DNL)。NAFLD的一个中心异常是新生脂肪生成增强。NAFLD患者的肝脏新生脂肪生成增加，而膳食脂肪和血浆FFA对肝脂的贡献没有明显改变。DNL在NAFLD中的重要性在小鼠研究中进一步得到证实，敲除了这一过程中涉及的基因。饮食中的果糖增加DNL相关酶的水平甚至比HFD更强烈。果糖代谢的几个特性使其特别容易产生脂肪。与其他组织相比，果糖通过门静脉被吸收，并以更高的浓度输送到肝脏。果糖在转化为甘油三酯的过程中会增加所有DNL酶的蛋白质水平。此外，在胰岛素抵抗的情况下，果糖支持脂肪生成，因为果糖的代谢不需要胰岛素，它直接刺激SREBP1c，SREBP1c是DNL的主要转录调节因子。果糖还会导致ATP耗竭和抑制线粒体脂肪酸氧化，从而增加活性氧物种的产生。此外，果糖促进内质网应激和尿酸的形成，这是导致DNL的额外的胰岛素非依赖性途径。综上所述，果糖代谢对DNL的支持作用强于HFD，肝脏DNL是NAFLD的中枢性异常。阻断肝脏中的果糖代谢可能为治疗NAFLD提供新的治疗选择。
Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome. Overconsumption of high-fat diet (HFD) and increased intake of sugar sweetened beverages are major risk-factors for development of NAFLD. Today the most commonly consumed sugar is high fructose corn syrup. Hepatic lipids may be derived from dietary intake, esterification of plasma free fatty acids (FFA) or hepatic de novo lipogenesis (DNL). A central abnormality in NAFLD is enhanced de novo lipogenesis. Hepatic de novo lipogenesis is increased in individuals with NAFLD, while the contribution of dietary fat and plasma FFA to hepatic lipids is not significantly altered. The importance of DNL in NAFLD is further established in mouse studies with knockout of genes involved in this process. Dietary fructose increases levels of enzymes involved in DNL even more strongly than HFD. Several properties of fructose metabolism make it particularly lipogenic. Fructose is absorbed via portal vein and delivered to the liver in much higher concentrations as compared to other tissues. Fructose increases protein levels of all DNL enzymes during its conversion into triglycerides. Additionally, fructose supports lipogenesis in the setting of insulin resistance as fructose does not require insulin for its metabolism and it directly stimulates SREBP1c, a major transcriptional regulator of DNL. Fructose also leads to ATP depletion and suppression of mitochondrial fatty acid oxidation resulting in increased production of reactive oxygen species. Furthermore fructose promotes ER stress and uric acid formation, additional insulin independent pathways leading to DNL. In summary, fructose metabolism supports DNL more strongly than HFD and hepatic DNL is a central abnormality in NAFLD. Disrupting fructose metabolism in the liver may provide a new therapeutic option for the treatment of NAFLD.