title: Organelle stress-induced activating transcription factor-3 downregulates low-density lipoprotein receptor expression in Sk-Hep1 human liver cells.
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.
authors.affiliation: Division of Metabolic Disease, Center for Biomedical Sciences, Korea National Institute of Health, 187 Osongsaengmyeong2-ro, Gangoe-myeon, Cheongwon-gun, Chungcheongbuk-do, Republic of Korea.
authors.forename: Joo Hyun
authors.initials: JH
authors.lastname: Lim
authors.forename: Hyo Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Youngmi Kim
authors.initials: YK
authors.lastname: Pak
authors.forename: Won-Ho
authors.initials: WH
authors.lastname: Kim
authors.forename: Jihyun
authors.initials: J
authors.lastname: Song
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D020029:Base Pairing; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics / Q000473:pathology; D008099:Liver / Q000166:cytology* / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics*
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D011973:Receptors, LDL