title: Activation of mTORC1 disrupted LDL receptor pathway: a potential new mechanism for the progression of non-alcoholic fatty liver disease.
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.
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing City, Jiangsu Province, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing City, Jiangsu Province, China. Electronic address: klma05@163.com.
authors.forename: Kun Ling
authors.initials: KL
authors.lastname: Ma
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing City, Jiangsu Province, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing City, Jiangsu Province, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing City, Jiangsu Province, China.
authors.forename: Ze Bo
authors.initials: ZB
authors.lastname: Hu
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing City, Jiangsu Province, China.
authors.forename: Lin Li
authors.initials: LL
authors.lastname: Lv
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing City, Jiangsu Province, China.
authors.forename: Ri Ning
authors.initials: RN
authors.lastname: Tang
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing City, Jiangsu Province, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, UK.
authors.forename: Xiong Zhong
authors.initials: XZ
authors.lastname: Ruan
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing City, Jiangsu Province, China.
authors.forename: Bi Cheng
authors.initials: BC
authors.lastname: Liu
mesh_terms: D000818:Animals; D018450:Disease Progression; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology; D011973:Receptors, LDL / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
chemical_list: D046912:Multiprotein Complexes; D011973:Receptors, LDL; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: Cholesterol homeostasis; Inflammation; Low density lipoprotein receptor; Mammalian target of rapamycin complex 1; Non-alcoholic fatty liver disease