ACBP knockdown leads to down-regulation of genes encoding rate-limiting enzymes in cholesterol and fatty acid metabolism.
The human Acyl-CoA binding protein (ACBP) is a structural and functional highly conserved protein. As an intracellular pool former and carrier of acyl-CoAs, ACBP influences overall lipid metabolism. Its nuclear abundance and physical interaction with hepatocyte nuclear factor 4alpha suggested a gene regulatory function of ACBP. To identify ACBP target genes we performed genome-wide transcript profiling under siRNA-mediated ACBP knockdown in human liver HepG2 cells. Based on a single sided permutation T-test (p<0.05) we identified 256 down-regulated and 198 up-regulated transcripts with a minimal fold change of 1.32 (log 0.5). Gene annotation enrichment analysis revealed ACBP-mediated down-regulation of 18 genes encoding key enzymes in glycerolipid (i.e. mitochondrial glycerol-3-phosphate acyltransferase), cholesterol (i.e. HMG-CoA synthase and HMG-CoA reductase) and fatty acid (i.e. fatty acid synthase) metabolism. Integration of these genes in common pathways suggested decreased lipid biosynthesis. Accordingly, saturated (16:0) and monosaturated (16:1, 18:1) fatty acids were significantly reduced to 75% in ACBP-depleted cells. Taken together, we obtained evidence that ACBP functions in lipid metabolism at the level of gene expression. This effect seems to be translated into certain metabolites. The identified 454 ACBP regulated genes present a first reference for further studies to define the ACBP regulon in mammalian cells.
Molecular Prevention, Christian-Albrechts-University of Kiel, D-24118 Kiel, Germany. sek@molprev.uni-kiel.de
Christina
C
Vock
Katrin
K
Biedasek
Inka
I
Boomgaarden
Anja
A
Heins
Inke
I
Nitz
Frank
F
Döring
D017209:Apoptosis; D002784:Cholesterol / Q000378:metabolism*; D026261:Diazepam Binding Inhibitor / Q000378:metabolism*; D015536:Down-Regulation; D005227:Fatty Acids / Q000378:metabolism*; D005796:Genes; D056945:Hep G2 Cells; D006801:Humans; D034741:RNA, Small Interfering / Q000235:genetics
D026261:Diazepam Binding Inhibitor; D005227:Fatty Acids; D034741:RNA, Small Interfering; D002784:Cholesterol