Organelle stress-induced activating transcription factor-3 downregulates low-density lipoprotein receptor expression in Sk-Hep1 human liver cells
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Joo Hyun Lim
Abstract
The low-density lipoprotein receptor (LDLR) plays a central role in cholesterol homeostasis. Here, we provide evidence that an increase in endoplasmic reticulum (ER) stress response or a disturbance of mitochondrial function inhibits LDLR expression in human liver Sk-Hep1 cells. Both organelle stresses triggered activation of activating transcription factor-3 (ATF3), which subsequently reduced LDLR expression. Serial deletion studies revealed that the LDLR promoter region within -234 bp was involved in the repression of LDLR by ATF3. In addition, we identified the region between -8 and -3 of LDLR promoter region as a putative binding site for ATF3 by using deletion construct lacking 6 bp nucleotide corresponding to this region. Transfection of ATF3-specific siRNA rescued LDLR expression under organelle stress, indicating that ATF3 was mainly responsible for the repression of LDLR by these stressors. Additionally, chromatin immunoprecipitation revealed that ATF3 directly binds to the LDLR promoter in a stress-dependent manner. The unique sterol-independent LDLR repression by organelle stress via ATF3 demonstrated here could be involved in obesity-related hypercholesterolemia, which can lead to insulin resistance and type 2 diabetes.
©2011 by Walter de Gruyter Berlin New York
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Articles in the same Issue
- Guest Editorial
- Highlight: Mechanisms of RNA-mediated regulation
- HIGHLIGHT: 62ND MOSBACH COLLOQUIUM OF THE GBM ‘MECHANISMS OF RNA-MEDIATED REGULATION’
- Clustered regularly interspaced short palindromic repeats (CRISPRs): the hallmark of an ingenious antiviral defense mechanism in prokaryotes
- Regulatory RNAs in cyanobacteria: developmental decisions, stress responses and a plethora of chromosomally encoded cis-antisense RNAs
- RNA-dependent RNA polymerases in RNA silencing
- Traces of post-transcriptional RNA modifications in deep sequencing data
- Allele-selective inhibition of ataxin-3 (ATX3) expression by antisense oligomers and duplex RNAs
- PROTEIN STRUCTURE AND FUNCTION
- The effects of a plant proteinase inhibitor from Enterolobium contortisiliquum on human tumor cell lines
- Role of unique basic residues in cytotoxic, antibacterial and antiparasitic activities of human eosinophil cationic protein
- Antiangiogenic kringles derived from human plasminogen and apolipoprotein(a) inhibit fibrinolysis through a mechanism that requires a functional lysine-binding site
- Changing nucleotide specificity of the DEAD-box helicase Hera abrogates communication between the Q-motif and the P-loop
- Identification of plasma haptoglobin forms which loosely bind hemoglobin
- MOLECULAR MEDICINE
- Organelle stress-induced activating transcription factor-3 downregulates low-density lipoprotein receptor expression in Sk-Hep1 human liver cells
- CELL BIOLOGY AND SIGNALING
- Helicobacter pylori-induced tyrosine phosphorylation of IKKβ contributes to NF-κB activation
