title: Rapamycin-mediated CD36 translational suppression contributes to alleviation of hepatic steatosis.
abstract: Rapamycin, a mammalian target of rapamycin (mTOR)-specific inhibitor, has the effect of anti-lipid deposition on non-alcoholic fatty liver disease (NAFLD), but the mechanisms with which rapamycin alleviates hepatic steatosis are not fully disclosed. CD36 is known to facilitate long-chain fatty acid uptake and contribute to NAFLD progression. Hepatic CD36 expression is closely associated with hepatic steatosis, while mTOR pathway is involved in CD36 translational control. This study was undertaken to investigate whether rapamycin alleviates hepatic steatosis via the inhibition of mTOR pathway-dependent CD36 translation. Human hepatoblastoma HepG2 cells were treated with palmitate and C57BL/6J mice were fed with high fat diet (HFD) to induce hepatic steatosis. Hepatic CD36 protein expression was significantly increased with lipid accumulation in palmitate-treated HepG2 cells or HFD-fed C57BL/6J mice. Rapamycin reduced hepatic steatosis and CD36 protein expression, but it had no influence on CD36 mRNA expression. Rapamycin had no effect on CD36 protein stability, but it significantly decreased CD36 translational efficiency. We further confirmed that rapamycin inhibited the phosphorylation of mTOR and its downstream translational regulators including p70 ribosomal protein S6 kinase (p70S6K), eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), and eukaryotic initiation factor 4E (eIF4E). This study demonstrates that rapamycin inhibits hepatic CD36 translational efficiency through the mTOR pathway, resulting in reduction of CD36 protein expression and alleviation of hepatic steatosis.
authors.affiliation: Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. Electronic address: myky2011@163.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Hu
authors.affiliation: Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: John Moorhead Research Laboratory, Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, University College London, London NW3 2PF, UK.
authors.forename: John F
authors.initials: JF
authors.lastname: Moorhead
authors.affiliation: John Moorhead Research Laboratory, Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, University College London, London NW3 2PF, UK.
authors.forename: Zac
authors.initials: Z
authors.lastname: Varghese
authors.affiliation: Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. Electronic address: chenyaxi@cqmu.edu.cn.
authors.forename: Yaxi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. Electronic address: x.ruan@ucl.ac.uk.
authors.forename: Xiong Z
authors.initials: XZ
authors.lastname: Ruan
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000096:biosynthesis*; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000188:drug therapy*; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D010168:Palmitates / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D018955:CD36 Antigens; D010168:Palmitates; D020123:Sirolimus
keywords: CD36; NAFLD; Rapamycin; Translation; mTOR