Medina Marisa W, Bauzon Frederick, Naidoo Devesh, Theusch Elizabeth, Stevens Kristen, Schilde Jessica, Schubert Christian, Mangravite Lara M, Rudel Lawrence L, Temel Ryan E, Runz Heiko, Krauss Ronald M
From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.).
Arterioscler Thromb Vasc Biol. 2014 Sep;34(9):1917-23. doi: 10.1161/ATVBAHA.113.302806. Epub 2014 Jul 17.
Interindividual variation in pathways affecting cellular cholesterol metabolism can influence levels of plasma cholesterol, a well-established risk factor for cardiovascular disease. Inherent variation among immortalized lymphoblastoid cell lines from different donors can be leveraged to discover novel genes that modulate cellular cholesterol metabolism. The objective of this study was to identify novel genes that regulate cholesterol metabolism by testing for evidence of correlated gene expression with cellular levels of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) mRNA, a marker for cellular cholesterol homeostasis, in a large panel of lymphoblastoid cell lines.
Expression array profiling was performed on 480 lymphoblastoid cell lines established from participants of the Cholesterol and Pharmacogenetics (CAP) statin clinical trial, and transcripts were tested for evidence of correlated expression with HMGCR as a marker of intracellular cholesterol homeostasis. Of these, transmembrane protein 55b (TMEM55B) showed the strongest correlation (r=0.29; P=4.0E-08) of all genes not previously implicated in cholesterol metabolism and was found to be sterol regulated. TMEM55B knockdown in human hepatoma cell lines promoted the decay rate of the low-density lipoprotein receptor, reduced cell surface low-density lipoprotein receptor protein, impaired low-density lipoprotein uptake, and reduced intracellular cholesterol.
Here, we report identification of TMEM55B as a novel regulator of cellular cholesterol metabolism through the combination of gene expression profiling and functional studies. The findings highlight the value of an integrated genomic approach for identifying genes that influence cholesterol homeostasis.
影响细胞胆固醇代谢的途径存在个体差异，这可能会影响血浆胆固醇水平，而血浆胆固醇是心血管疾病公认的危险因素。不同供体的永生化淋巴母细胞系之间的固有差异可用于发现调节细胞胆固醇代谢的新基因。本研究的目的是通过检测一大组淋巴母细胞系中与3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）mRNA细胞水平相关基因表达的证据，来鉴定调节胆固醇代谢的新基因，HMGCR mRNA是细胞胆固醇稳态的一个标志物。
对从胆固醇与药物遗传学（CAP）他汀类药物临床试验参与者建立的480个淋巴母细胞系进行表达阵列分析，并检测转录本与作为细胞内胆固醇稳态标志物的HMGCR相关表达的证据。其中，跨膜蛋白55b（TMEM55B）在所有先前未涉及胆固醇代谢的基因中显示出最强的相关性（r = 0.29；P = 4.0E - 08），并且发现其受固醇调节。在人肝癌细胞系中敲低TMEM55B可促进低密度脂蛋白受体的降解速率，降低细胞表面低密度脂蛋白受体蛋白水平，损害低密度脂蛋白摄取，并降低细胞内胆固醇。
在此，我们通过基因表达谱分析和功能研究相结合的方法，报告鉴定出TMEM55B是细胞胆固醇代谢的一种新型调节因子。这些发现突出了综合基因组方法在鉴定影响胆固醇稳态基因方面的价值。
