Fernandez Céline, Lindholm Marie, Krogh Morten, Lucas Stéphanie, Larsson Sara, Osmark Peter, Berger Karin, Borén Jan, Fielding Barbara, Frayn Keith, Holm Cecilia
Department of Experimental Medical Science, Lund University, BMC C11, SE-221 84 Lund, Sweden.
Am J Physiol Endocrinol Metab. 2008 Oct;295(4):E820-31. doi: 10.1152/ajpendo.90206.2008. Epub 2008 Jul 29.
Transcriptomics analysis revealed that genes involved in hepatic de novo cholesterol synthesis were downregulated in fed HSL-null mice that had been on a high-fat diet (HFD) for 6 mo. This finding prompted a further analysis of cholesterol metabolism in HSL-null mice, which was performed in fed and 16-h-fasted mice on a normal chow diet (ND) or HFD regimen. Plasma cholesterol was elevated in HSL-null mice, in all tested conditions, as a result of cholesterol enrichment of HDL and VLDL. Hepatic esterified cholesterol content and ATP-binding cassette transporter A1 (ABCA1) mRNA and protein levels were increased in HSL-null mice regardless of the dietary regimen. Unsaturated fatty acid composition of hepatic triglycerides was modified in fasted HSL-null mice on ND and HFD. The increased ABCA1 expression had no major effect on cholesterol efflux from HSL-null mouse hepatocytes. Taken together, the results of this study suggest that HSL plays a critical role in the hydrolysis of cytosolic cholesteryl esters and that increased levels of hepatic cholesteryl esters, due to lack of action of HSL in the liver, are the main mechanism underlying the imbalance in cholesterol metabolism in HSL-null mice.
转录组学分析显示，在高脂饮食（HFD）喂养6个月的HSL基因敲除小鼠中，参与肝脏胆固醇从头合成的基因表达下调。这一发现促使对HSL基因敲除小鼠的胆固醇代谢进行进一步分析，该分析在正常饮食（ND）或HFD喂养方案下的喂食小鼠和禁食16小时的小鼠中进行。在所有测试条件下，由于高密度脂蛋白（HDL）和极低密度脂蛋白（VLDL）中胆固醇含量增加，HSL基因敲除小鼠的血浆胆固醇升高。无论饮食方案如何，HSL基因敲除小鼠肝脏中酯化胆固醇含量以及ATP结合盒转运蛋白A1（ABCA1）的mRNA和蛋白质水平均升高。在正常饮食和高脂饮食条件下禁食的HSL基因敲除小鼠肝脏甘油三酯的不饱和脂肪酸组成发生了改变。ABCA1表达增加对HSL基因敲除小鼠肝细胞的胆固醇流出没有显著影响。综上所述，本研究结果表明，HSL在细胞溶质胆固醇酯的水解中起关键作用，并且由于肝脏中HSL缺乏作用导致肝脏胆固醇酯水平升高，是HSL基因敲除小鼠胆固醇代谢失衡的主要机制。
