Adipose differentiation-related protein is not involved in hypoxia inducible factor-1-induced lipid accumulation under hypoxia

Shen,Guomin; Ning,Ning; Zhao,Xingsheng; Liu,Xi; Wang,Guangyu; Wang,Tianzhen; Zhao,Ran; Yang,Chao; Wang,Dongmei; Gong,Pingyuan; Shen,Yan; Sun,Yongjian; Zhao,Xiao; Jin,Yinji; Yang,Weiwei; He,Yan; Zhang,Lei; Jin,Xiaoming; Li,Xiaobo

doi:10.3892/mmr.2015.4488

Adipose differentiation-related protein is not involved in hypoxia inducible factor-1-induced lipid accumulation under hypoxia

Authors:
- Guomin Shen
- Ning Ning
- Xingsheng Zhao
- Xi Liu
- Guangyu Wang
- Tianzhen Wang
- Ran Zhao
- Chao Yang
- Dongmei Wang
- Pingyuan Gong
- Yan Shen
- Yongjian Sun
- Xiao Zhao
- Yinji Jin
- Weiwei Yang
- Yan He
- Lei Zhang
- Xiaoming Jin
- Xiaobo Li
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Affiliations: Department of Medical Genetics, Medical College, Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China, Department of Gastrointestinal Surgery, International Hospital of Peking University, Beijing 100871, P.R. China, Department of Cardiovascular Disease, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia 010070, P.R. China, Department of Gastrointestinal Medical Oncology, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, Heilongjiang 100036, P.R. China, Department of Pathology, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
Published online on: October 26, 2015 https://doi.org/10.3892/mmr.2015.4488
Pages: 8055-8061
Copyright: © Shen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Increasing evidence has showed that hypoxia inducible factor-1 (HIF1) has an important role in hypoxia-induced lipid accumulation, a common feature of solid tumors; however, its role remains to be fully elucidated. Adipose differentiation‑related protein (ADRP), a structural protein of lipid droplets, is found to be upregulated under hypoxic conditions. In the present study, an MCF7 breast cancer cell line was used to study the role of ADRP in hypoxia‑induced lipid accumulation. It was demonstrated that hypoxia induced the gene expression of ADRP in a HIF1‑dependent manner. Increases in the mRNA and protein levels of ADRP was accompanied by increased HIF1A activity. In addition, a significant decrease in the mRNA and protein levels of ADRP were detected in presence of siRNA targeting HIF1A. Using a dual‑luciferase reporting experiment and chromatin immunoprecipitation assay, the present study demonstrated that ADRP is a direct target gene of HIF1, and identified a functional hypoxia response element localized 33 bp upstream of the transcriptional start site of the ADRP gene. Furthermore, the present study demonstrated the role of ADRP in low density liporotein (LDL) and very‑LDL uptake‑induced lipid accumulation under hypoxia. The knockdown of ADRP did not reduce HIF1‑induced lipid accumulation under hypoxia. Together, these results showed that ADRP may be not involved in HIF1-induced lipid accumulation.

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1	Wang GL, Jiang BH, Rue EA and Semenza GL: Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA. 92:5510–5514. 1995. View Article : Google Scholar : PubMed/NCBI
2	Semenza GL: Hypoxia-inducible factors in physiology and medicine. Cell. 148:399–408. 2012. View Article : Google Scholar : PubMed/NCBI
3	Semenza GL: Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 29:625–634. 2010. View Article : Google Scholar :
4	Scarfo LM, Weller PF and Farber HW: Induction of endothelial cell cytoplasmic lipid bodies during hypoxia. Am J Physiol Heart Circ Physiol. 280:H294–H301. 2001.
5	Belanger AJ, Luo Z, Vincent KA, Akita GY, Cheng SH, Gregory RJ and Jiang C: Hypoxia-inducible factor 1 mediates hypoxia-induced cardiomyocyte lipid accumulation by reducing the DNA binding activity of peroxisome proliferator-activated receptor alpha/retinoid X receptor. Biochem Biophys Res Commun. 364:567–572. 2007. View Article : Google Scholar : PubMed/NCBI
6	Chabowski A, Gorski J, Calles-Escandon J, Tandon NN and Bonen A: Hypoxia-induced fatty acid transporter translocation increases fatty acid transport and contributes to lipid accumulation in the heart. FEBS Lett. 580:3617–3623. 2006. View Article : Google Scholar : PubMed/NCBI
7	Imamura M, Inoguchi T, Ikuyama S, Taniguchi S, Kobayashi K, Nakashima N and Nawata H: ADRP stimulates lipid accumulation and lipid droplet formation in murine fibroblasts. Am J Physiol Endocrinol Metab. 283:E775–E783. 2002. View Article : Google Scholar : PubMed/NCBI
8	Larigauderie G, Furman C, Jaye M, Lasselin C, Copin C, Fruchart JC, Castro G and Rouis M: Adipophilin enhances lipid accumulation and prevents lipid efflux from THP-1 macrophages: Potential role in atherogenesis. Arterioscler Thromb Vasc Biol. 24:504–510. 2004. View Article : Google Scholar : PubMed/NCBI
9	Paul A, Chang BH, Li L, Yechoor VK and Chan L: Deficiency of adipose differentiation-related protein impairs foam cell formation and protects against atherosclerosis. Circ Res. 102:1492–1501. 2008. View Article : Google Scholar : PubMed/NCBI
10	Saarikoski ST, Rivera SP and Hankinson O: Mitogen-inducible gene 6 (MIG-6), adipophilin and tuftelin are inducible by hypoxia. FEBS Lett. 530:186–190. 2002. View Article : Google Scholar : PubMed/NCBI
11	Xia X, Lemieux ME, Li W, Carroll JS, Brown M, Liu XS and Kung AL: Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis. Proc Natl Acad Sci USA. 106:4260–4265. 2009. View Article : Google Scholar : PubMed/NCBI
12	Bostrom P, Magnusson B, Svensson PA, Wiklund O, Borén J, Carlsson LM, Ståhlman M, Olofsson SO and Hultén LM: Hypoxia converts human macrophages into triglyceride-loaded foam cells. Arterioscler Thromb Vasc Biol. 26:1871–1876. 2006. View Article : Google Scholar : PubMed/NCBI
13	Shen GM, Zhao YZ, Chen MT, Zhang FL, Liu XL, Wang Y, Liu CZ, Yu J and Zhang JW: Hypoxia-inducible factor-1 (HIF-1) promotes LDL and VLDL uptake through inducing VLDLR under hypoxia. Biochem J. 441:675–683. 2012. View Article : Google Scholar
14	Wang GL and Semenza GL: Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J Biol Chem. 268:21513–21518. 1993.PubMed/NCBI
15	Li X, Zhang J, Gao L, McClellan S, Finan MA, Butler TW, Owen LB, Piazza GA and Xi Y: MiR-181 mediates cell differentiation by interrupting the Lin28 and let-7 feedback circuit. Cell Death Differ. 19:378–386. 2012. View Article : Google Scholar :
16	Pescador N, Villar D, Cifuentes D, Garcia-Rocha M, Ortiz-Barahona A, Vazquez S, Ordoñez A, Cuevas Y, Saez-Morales D, Garcia-Bermejo ML, et al: Hypoxia promotes glycogen accumulation through hypoxia inducible factor (HIF)-mediated induction of glycogen synthase 1. PLoS One. 5:e96442010. View Article : Google Scholar : PubMed/NCBI
17	Shen GM, Zhang FL, Liu XL and Zhang JW: Hypoxia-inducible factor 1-mediated regulation of PPP1R3C promotes glycogen accumulation in human MCF-7 cells under hypoxia. FEBS Lett. 584:4366–4372. 2010. View Article : Google Scholar : PubMed/NCBI
18	Straub BK, Herpel E, Singer S, Zimbelmann R, Breuhahn K, Macher-Goeppinger S, Warth A, Lehmann-Koch J, Longerich T, Heid H and Schirmacher P: Lipid droplet-associated PAT-proteins show frequent and differential expression in neoplastic steatogenesis. Mod Pathol. 23:480–492. 2010. View Article : Google Scholar : PubMed/NCBI
19	Ostler DA, Prieto VG, Reed JA, Deavers MT, Lazar AJ and Ivan D: Adipophilin expression in sebaceous tumors and other cutaneous lesions with clear cell histology: An immunohistochemical study of 117 cases. Mod Pathol. 23:567–573. 2010. View Article : Google Scholar : PubMed/NCBI
20	Wada Y, Sugiyama A, Yamamoto T, Naito M, Noguchi N, Yokoyama S, Tsujita M, Kawabe Y, Kobayashi M, Izumi A, et al: Lipid accumulation in smooth muscle cells under LDL loading is independent of LDL receptor pathway and enhanced by hypoxic conditions. Arterioscler Thromb Vasc Biol. 22:1712–1719. 2002. View Article : Google Scholar : PubMed/NCBI
21	Castellano J, Aledo R, Sendra J, Costales P, Juan-Babot O, Badimon L and Llorente-Cortés V: Hypoxia stimulates low-density lipoprotein receptor-related protein-1 expression through hypoxia-inducible factor-1α in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 31:1411–1420. 2011. View Article : Google Scholar : PubMed/NCBI
22	Cal R, Castellano J, Revuelta-López E, Aledo R, Barriga M, Farré J, Vilahur G, Nasarre L, Hove-Madsen L, Badimon L and Llorente-Cortés V: Low-density lipoprotein receptor-related protein 1 mediates hypoxia-induced very low density lipoprotein-cholesteryl ester uptake and accumulation in cardiomyocytes. Cardiovasc Res. 94:469–479. 2012. View Article : Google Scholar : PubMed/NCBI
23	Perman JC, Boström P, Lindbom M, Lidberg U, StÅhlman M, Hägg D, Lindskog H, Scharin Täng M, Omerovic E, Mattsson Hultén L, et al: The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction. J Clin Invest. 121:2625–2640. 2011. View Article : Google Scholar : PubMed/NCBI
24	Castellano J, Farré J, Fernandes J, Bayes-Genis A, Cinca J, Badimon L, Hove-Madsen L and Llorente-Cortés V: Hypoxia exacerbates Ca(2+)-handling disturbances induced by very low density lipoproteins (VLDL) in neonatal rat cardiomyocytes. J Mol Cell Cardiol. 50:894–902. 2011. View Article : Google Scholar : PubMed/NCBI
25	Gimm T, Wiese M, Teschemacher B, Deggerich A, Schödel J, Knaup KX, Hackenbeck T, Hellerbrand C, Amann K, Wiesener MS, et al: Hypoxia-inducible protein 2 is a novel lipid droplet protein and a specific target gene of hypoxia-inducible factor-1. FASEB J. 24:4443–4458. 2010. View Article : Google Scholar : PubMed/NCBI