The present study was designed to test the hypothesis that in the liver, excessive fat accumulation impairs cholesterol metabolism mainly by altering the low-density lipoprotein-receptor (LDL-R) pathway. Young male Wistar rats were fed standard (SD), high fat (HFD; 60% kcal) or Western (WD; 40% fat + 35% sucrose (17.5% fructose)) diets for 2 or 6 weeks. Weight gain (~ 40 g) was observed only following 6 weeks of the obesogenic diets (P < 0.01). Compared to the 2-week treatment, obesogenic diets tripled fat pad weight (~ 20 vs 7 g) after 6 weeks. Hepatic triglyceride (TG) levels were greater in response to both the WD and HFD compared to the SD (P < 0.01) at 2 and 6 weeks and their concentrations were greater (P < 0.05) in WD than HFD at 2 weeks. Plasma total cholesterol levels were higher (P < 0.05) in animals submitted to WD. After 2 and 6 weeks, liver expression of LDL-R, proprotein convertase subtilisin/kexin 9 (PCSKk9) and sterol regulatory element binding protein 2 (SREBP2), involved in LDL-cholesterol uptake, was lower in animals submitted to WD than in others treated with HFD or SD (P < 0.01). Similarly, low-density lipoprotein-receptor-related protein 1 (LRP1) and acyl-CoA cholesterol acyltransferase-2 (ACAT-2) mRNA levels were lower (P < 0.01) among WD compared to SD-fed rats. Expression of the gene coding the main regulator of endogenous cholesterol synthesis, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoAR) was reduced in response to WD compared to SD and HFD at 2 (P < 0.001) and 6 (P < 0.05) weeks. Being enriched in fructose, the WD strongly promoted the expression of carbohydrate-response element binding protein (ChREBP) and acetyl-CoA carboxylase (ACC), two key regulators of de novo lipogenesis. These results show that the WD promptly increased TG levels in the liver by potentiating fat storage. This impaired the pathway of hepatic cholesterol uptake via the LDL-R axis, promoting a rapid increase in plasma total cholesterol levels. These results indicate that liver fat content is a factor involved in the regulation of plasma cholesterol.

中文翻译：

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西方饮食的两周破坏了大鼠胆固醇代谢的肝分子标记。

本研究旨在检验以下假设：肝脏中过多的脂肪积累主要通过改变低密度脂蛋白受体（LDL-R）途径来损害胆固醇代谢。年轻的雄性Wistar大鼠接受标准（SD），高脂肪（HFD; 60％kcal）或西方（WD; 40％脂肪+ 35％蔗糖（17.5％果糖））的饮食2或6周。仅在致肥胖饮食的6周后观察到体重增加（〜40 g）（P <0.01）。与2周的治疗相比，致肥胖症的饮食在6周后的脂肪垫重量增加了三倍（〜20 vs 7 g）。在2周和6周时，对WD和HFD的反应，肝甘油三酸酯（TG）水平均高于SD（P <0.01），而在2周时，WD中的甘油三酸脂浓度高于（FD）0.05（P <0.05）。接受WD治疗的动物血浆总胆固醇水平较高（P <0.05）。在第2周和第6周后，参与WD的动物的LDL-R，原蛋白转化酶枯草杆菌蛋白酶/ kexin 9（PCSKk9）和固醇调节元素结合蛋白2（SREBP2）的肝脏表达低于其他动物。用HFD或SD处理（P <0.01）。同样，与SD喂养的大鼠相比，WD中的低密度脂蛋白受体相关蛋白1（LRP1）和酰基辅酶A胆固醇酰基转移酶-2（ACAT-2）mRNA水平较低（P <0.01）。与SD和HFD相比，在2（P <0.001）和6（P时），编码内源性胆固醇合成的主要调节因子3-羟基-3-甲基-戊二酰-CoA还原酶（HMGCoAR）的基因的表达降低。 <0.05）周。富含果糖，WD强烈促进了碳水化合物反应元件结合蛋白（ChREBP）和乙酰辅酶A羧化酶（ACC）的表达，这是新生脂肪形成的两个关键调节因子。这些结果表明，WD通过增强脂肪储存而迅速增加了肝脏中的TG水平。这削弱了通过LDL-R轴吸收肝胆固醇的途径，从而促进血浆总胆固醇水平的快速增加。这些结果表明肝脂肪含量是血浆胆固醇调节的一个因素。