Consequences of Exchanging Carbohydrates for Proteins in the Cholesterol Metabolism of Mice Fed a High-fat Diet

Consumption of low-carbohydrate, high-protein, high-fat diets lead to rapid weight loss but the cardioprotective effects of these diets have been questioned. We examined the impact of high-protein and high-fat diets on cholesterol metabolism by comparing the plasma cholesterol and the expression of cholesterol biosynthesis genes in the liver of mice fed a high-fat (HF) diet that has a high (H) or a low (L) protein-to-carbohydrate (P/C) ratio. H-P/C-HF feeding, compared with L-P/C-HF feeding, decreased plasma total cholesterol and increased HDL cholesterol concentrations at 4-wk. Interestingly, the expression of genes involved in hepatic steroid biosynthesis responded to an increased dietary P/C ratio by first down-regulation (2-d) followed by later up-regulation at 4-wk, and the temporal gene expression patterns were connected to the putative activity of SREBF1 and 2. In contrast, Cyp7a1, the gene responsible for the conversion of cholesterol to bile acids, was consistently up-regulated in the H-P/C-HF liver regardless of feeding duration. Over expression of Cyp7a1 after 2-d and 4-wk H-P/C-HF feeding was connected to two unique sets of transcription regulators. At both time points, up-regulation of the Cyp7a1 gene could be explained by enhanced activations and reduced suppressions of multiple transcription regulators. In conclusion, we demonstrated that the hypocholesterolemic effect of H-P/C-HF feeding coincided with orchestrated changes of gene expressions in lipid metabolic pathways in the liver of mice. Based on these results, we hypothesize that the cholesterol lowering effect of high-protein feeding is associated with enhanced bile acid production but clinical validation is warranted. (246 words)低碳水化合物、高蛋白、高脂肪膳食的摄入可引发快速体重下降，但此类膳食的心脏保护作用却遭到了质疑。本研究通过对比饲喂高脂（HF）膳食且蛋白与碳水化合物（P/C）比值分别为高（H）、低（L）的小鼠的血浆胆固醇水平与肝脏胆固醇生物合成基因的表达情况，探究了高蛋白与高脂肪膳食对胆固醇代谢的影响。与低P/C比值高脂（L-P/C-HF）膳食饲喂相比，高P/C比值高脂（H-P/C-HF）膳食饲喂在第4周时可降低小鼠血浆总胆固醇水平，并提升高密度脂蛋白（HDL）胆固醇浓度。有趣的是，参与肝脏类固醇生物合成的基因表达对膳食P/C比值升高的响应呈现先下调（第2天）、后在第4周上调的模式，且该时序基因表达模式与固醇调节元件结合蛋白1、2（SREBF1、SREBF2）的推定活性相关。与之相反，负责将胆固醇转化为胆汁酸的胆固醇7α-羟化酶1（Cyp7a1）基因在H-P/C-HF饲喂组的小鼠肝脏中始终呈上调表达，且不受饲喂时长的影响。在饲喂H-P/C-HF膳食2天及4周后，Cyp7a1的表达上调与两组独特的转录调控因子存在关联。在这两个时间点，Cyp7a1基因的上调表达均可通过多种转录调控因子的激活增强与抑制减弱得到解释。综上，本研究证实，H-P/C-HF膳食饲喂的降胆固醇效应与小鼠肝脏脂质代谢通路中基因表达的协同调控变化相契合。基于上述研究结果，我们提出假说：高蛋白膳食的降胆固醇效应与胆汁酸生成增强相关，但仍需开展临床验证以确认该结论。(246词)