The Role of the Carbohydrate Response Element-Binding Protein in Male Fructose-Fed Rats
The Role of the Carbohydrate Response Element-Binding Protein in Male Fructose-Fed Rats
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DOI：
10.1210/en.2012-1725
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发表时间：
2013-01-01
期刊：
影响因子：
4.8
通讯作者：
Samuel, Varman T.
中科院分区：
文献类型：
--
作者：
Erion, Derek M.;Popov, Violetta;Samuel, Varman T.
到2030年，近一半的美国人将患有非酒精性脂肪肝。在某种程度上，这种流行病是由热量甜味剂的消费增加加上通过肝脏从头脂肪生成将糖转化为脂肪的先天能力所推动的。除了作为底物，单糖还通过碳水化合物反应元件结合蛋白（ChREBP）增加参与从头脂肪生成的关键酶的表达。为了确定ChREBP是否是一个潜在的治疗靶点，我们用特定的反义寡核苷酸（阿索）降低了喂食高果糖或高脂肪饮食的雄性Sprague-Dawley大鼠肝脏中ChREBP的表达。在两个饮食组中，与对照阿索治疗相比，ChREBP阿索治疗降低了血浆甘油三酯浓度。在果糖喂养组中，这种降低更为明显，这归因于ACC 2、FAS、SCD 1和MTTP的肝脏表达降低以及肝脏甘油三酯分泌速率降低。这与胰岛素刺激的外周葡萄糖摄取增加有关，如通过高胰岛素-正常血糖钳夹所评估的。相反，ChREBP阿索没有改变肝脏脂质含量或肝脏胰岛素敏感性。有趣的是，用ChREBP阿索治疗的果糖喂养大鼠的血浆尿酸、丙氨酸转氨酶和天冬氨酸转氨酶浓度增加。这与果糖醛缩酶和果糖激酶的表达减少有关，这让人联想到果糖代谢的遗传性疾病。总之，这些研究表明，靶向ChREBP可以预防果糖诱导的高甘油三酯血症，但不能改善肝脏脂肪变性和肝脏胰岛素反应性。（内分泌学154：36-44，2013）
By 2030, nearly half of Americans will have nonalcoholic fatty liver disease. In part, this epidemic is fueled by the increasing consumption of caloric sweeteners coupled with an innate capacity to convert sugar into fat via hepatic de novo lipogenesis. In addition to serving as substrates, monosaccharides also increase the expression of key enzymes involved in de novo lipogenesis via the carbohydrate response element-binding protein (ChREBP). To determine whether ChREBP is a potential therapeutic target, we decreased hepatic expression of ChREBP with a specific antisense oligonucleotide (ASO) in male Sprague-Dawley rats fed either a high-fructose or high-fat diet. ChREBP ASO treatment decreased plasma triglyceride concentrations compared with control ASO treatment in both diet groups. The reduction was more pronounced in the fructose-fed group and attributed to decreased hepatic expression of ACC2, FAS, SCD1, and MTTP and a decrease in the rate of hepatic triglyceride secretion. This was associated with an increase in insulin-stimulated peripheral glucose uptake, as assessed by the hyperinsulinemic-euglycemic clamp. In contrast, ChREBP ASO did not alter hepatic lipid content or hepatic insulin sensitivity. Interestingly, fructose-fed rats treated with ChREBP ASO had increased plasma uric acid, alanine transaminase, and aspartate aminotransferase concentrations. This was associated with decreased expression of fructose aldolase and fructokinase, reminiscent of inherited disorders of fructose metabolism. In summary, these studies suggest that targeting ChREBP may prevent fructose-induced hypertriglyceridemia but without the improvements in hepatic steatosis and hepatic insulin responsiveness. (Endocrinology 154: 36-44, 2013)