Identification of Cholesterol-Regulating Genes by Targeted RNAi Screening

被引：155

作者：

Bartz, Fabian ^{[1
,2
]}

Kern, Luise ^{[1
,2
]}

Erz, Dorothee ^{[2
]}

Zhu, Mingang ^{[1
,3
]}

Gilbert, Daniel ^{[5
]}

Meinhof, Till ^{[2
]}

Wirkner, Ute ^{[6
]}

Erfle, Holger ^{[4
,5
]}

Muckenthaler, Martina ^{[1
,3
]}

Pepperkok, Rainer ^{[1
,5
]}

Runz, Heiko ^{[1
,2
]}

机构：

[1] Heidelberg Univ, MMPU, EMBL, D-69117 Heidelberg, Germany

[2] Heidelberg Univ, Inst Human Genet, D-69117 Heidelberg, Germany

[3] Heidelberg Univ, Dept Pediat, D-69117 Heidelberg, Germany

[4] Heidelberg Univ, Viroquant Cell Networks RNAi Screening Facil, D-69117 Heidelberg, Germany

[5] EMBL, Cell Biol Biophys Unit, D-69117 Heidelberg, Germany

[6] German Canc Res Ctr, Dept Radiat Oncol, D-69120 Heidelberg, Germany

来源：

CELL METABOLISM | 2009年 / 10卷 / 01期

关键词：

LOW-DENSITY-LIPOPROTEIN; ELEMENT; BINDING; CELLS; RECEPTOR; RISK; ER; TRAFFICKING; TRANSFERRIN; MUTATION;

D O I：

10.1016/j.cmet.2009.05.009

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Elevated plasma cholesterol levels are considered responsible for excess cardiovascular morbidity and mortality. Cholesterol in plasma is tightly controlled by cholesterol within cells. Here, we developed and applied an integrative functional genomics strategy that allows systematic identification of regulators of cellular cholesterol levels. Candidate genes were identified by genome-wide gene-expression profiling of sterol-depleted cells and systematic literature queries. The role of these genes in cholesterol regulation was then tested by targeted siRNA knockdown experiments quantifying cellular cholesterol levels and the efficiency of low-density lipoprotein (LDL) uptake. With this strategy, 20 genes were identified as functional regulators of cellular cholesterol homeostasis. Of these, we describe TMEM97 as SREBP target gene that under sterol-depleted conditions localizes to endo-/lysosomal compartments and binds to LDL cholesterol transport-regulating protein Niemann-Pick C1 (NPC1). Taken together, TMEM97 and other factors described here are promising to yield further insights into how cells control cholesterol levels.

引用

页码：63 / 75

页数：13

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