Activation of mTORC1 disrupted LDL receptor pathway: A potential new mechanism for the progression of non-alcoholic fatty liver disease |
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| Affiliation: | 1. Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing City, Jiangsu Province, China;2. Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, UK;3. Division of Pediatric Rheumatology, Children''s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104;4. Immunology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania 19104;5. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104;1. Department of Pathology, National University Hospital, National University Health System, Singapore;2. Department of Haematology-Oncology, National University Hospital, National University Health System, Singapore;1. Department of General, Visceral- and Transplantation Surgery, Faculty of Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany;2. Department of Gastroenterology and Hepatology, Faculty of Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany;3. Institute of Pharmacology and Toxicology, School of Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany;4. Institute of Pharmacogenetics, Faculty of Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany;1. UMR 1019 Nutrition Humaine, INRA, Université Clermont 1, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France;2. Centre des Sciences du Goût et de l’Alimentation, UMR 6265-CNRS/1324-INRA, Université de Bourgogne, 21000 Dijon, France;3. STROMAlab, UMR 5273-CNRS Université Paul Sabatier, EFS, U1031 INSERM, BP 84225, 31432 Toulouse Cedex 4, France;4. University of Cambridge, Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Center, Cambridge CB2 0QQ, UK;1. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA;2. Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA |
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| Abstract: | Our previous studies demonstrated that inflammation exacerbates the progression of non-alcoholic fatty liver disease (NAFLD) by disrupting cholesterol homeostasis. This study aimed to investigate the role of mammalian target of rapamycin complex 1 (mTORC1) in NAFLD under conditions of inflammation. Chronic inflammation was induced by using subcutaneous injections of 10% casein in apolipoprotein E knockout (ApoE KO) mice in vivo and interleukin-1β stimulation of the HepG2 hepatoblastoma cell line in vitro. Results demonstrated that inflammation increased lipid accumulation in HepG2 cells and in livers of apolipoprotein E knockout mice. These effects were correlated with an increase in low density lipoprotein receptor (LDLR) gene transcription, which was mediated through the up-regulation of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), SREBP-2, and through enhanced translocation of the SCAP/SREBP-2 complex from endoplasmic reticulum (ER) to Golgi. In addition, our data indicated that inflammation down-regulated the expression of proprotein convertase subtilisin kexin 9 (PCSK9) and prevented the degradation of LDLR protein via posttranscriptional mechanisms. Further analysis showed that inflammation increased the protein phosphorylation of mTOR, eukaryotic initiation factor 4E-binding protein 1, and p70 S6 kinase. Interestingly, blocking mTORC1 activity inhibited the translocation of SCAP/SREBP-2 complex from the ER to the Golgi and decreased the expression of LDLR, SCAP, and SREBP-2. These effects were accompanied by an increase in the expression of PCSK9 and accelerated LDLR degradation. Our findings demonstrated that increased mTORC1 activity exacerbated the progression of NAFLD by disrupting LDLR expression via transcriptional and posttranscriptional mechanisms. |
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| Keywords: | Inflammation Mammalian target of rapamycin complex 1 Low density lipoprotein receptor Non-alcoholic fatty liver disease Cholesterol homeostasis |
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