Arterioscler Thromb Vasc Biol 2014 Sep 17;34(9):1917-23. Epub 2014 Jul 17.
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.).
Objective: 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.
Approach And Results: 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.
Conclusions: 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.