Yu Wu1, Kun L Ma2, Yang Zhang1, Yi Wen1, Gui H Wang1, Ze B Hu1, Liang Liu1, Jian Lu1, Pei P Chen1, Xiong Z Ruan3, Bi C Liu1. 1. Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing City, Jiangsu Province, China. 2. Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing City, Jiangsu Province, China. klma05@163.com. 3. Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, London, UK.
Abstract
BACKGROUND: This study aimed to investigate the possible synergistic effects of lipid disorder with renin-angiotensin system (RAS) activation in non-alcoholic fatty liver disease (NAFLD). METHODS: Apolipoprotein E gene-knockout mice, angiotensin II (Ang II) type 1 receptor (AT1) gene-knockout mice and human hepatoblastoma cell line (HepG2) were used for experiments. Lipid accumulation was examined by Filipin staining and intracellular cholesterol quantitative assay. The gene and protein expression of molecules involved in RAS and low-density lipoprotein receptor (LDLr) pathway was examined by real-time PCR, immunofluorescent staining and Western blot. RESULTS: There was significantly increased expression of RAS components and extracellular matrix (ECM) in livers of high-fat-diet-fed apolipoprotein E gene-knockout mice compared with controls. Upregulation of RAS components was positively associated with increased plasma levels of lipid profile. The in vitro study further confirmed that cholesterol loading increased supernatant renin activity and Ang II level of HepG2 cells, accompanied by increased ECM production that was positively associated with increased expression of intracellular RAS components. Interestingly, Ang II treatment increased lipid accumulation in livers of C57BL/6 mice and HepG2 cells. Furthermore, Ang II treatment increased gene and protein expression of sterol regulatory element-binding protein (SREBP) cleavage activating protein (SCAP), SREBP-2 and LDLr, which were mediated by enhanced SCAP/SREBP-2 complex translocation from endoplasmic reticulum to Golgi. However, LDLr pathway was accordingly downregulated in livers of AT1 gene-knockout C57BL/6 mice or in HepG2 cells treated by telmisartan. CONCLUSION: These findings demonstrate that lipid disorder and intrahepatic RAS activation synergistically accelerate NAFLD progression.
BACKGROUND: This study aimed to investigate the possible synergistic effects of lipid disorder with renin-angiotensin system (RAS) activation in non-alcoholic fatty liver disease (NAFLD). METHODS:Apolipoprotein E gene-knockout mice, angiotensin II (Ang II) type 1 receptor (AT1) gene-knockout mice and humanhepatoblastoma cell line (HepG2) were used for experiments. Lipid accumulation was examined by Filipin staining and intracellular cholesterol quantitative assay. The gene and protein expression of molecules involved in RAS and low-density lipoprotein receptor (LDLr) pathway was examined by real-time PCR, immunofluorescent staining and Western blot. RESULTS: There was significantly increased expression of RAS components and extracellular matrix (ECM) in livers of high-fat-diet-fed apolipoprotein E gene-knockout mice compared with controls. Upregulation of RAS components was positively associated with increased plasma levels of lipid profile. The in vitro study further confirmed that cholesterol loading increased supernatant renin activity and Ang II level of HepG2 cells, accompanied by increased ECM production that was positively associated with increased expression of intracellular RAS components. Interestingly, Ang II treatment increased lipid accumulation in livers of C57BL/6 mice and HepG2 cells. Furthermore, Ang II treatment increased gene and protein expression of sterol regulatory element-binding protein (SREBP) cleavage activating protein (SCAP), SREBP-2 and LDLr, which were mediated by enhanced SCAP/SREBP-2 complex translocation from endoplasmic reticulum to Golgi. However, LDLr pathway was accordingly downregulated in livers of AT1 gene-knockout C57BL/6 mice or in HepG2 cells treated by telmisartan. CONCLUSION: These findings demonstrate that lipid disorder and intrahepatic RAS activation synergistically accelerate NAFLD progression.
Authors: Ana Cristina Simões E Silva; Aline S Miranda; Natália P Rocha; Antônio L Teixeira Journal: World J Gastroenterol Date: 2017-05-21 Impact factor: 5.742
Authors: Jung Gyu Park; Jong Soo Mok; Young In Han; Tae Sub Park; Keon Wook Kang; Cheol Soo Choi; Hee Dong Park; Joonghoon Park Journal: Sci Rep Date: 2019-03-08 Impact factor: 4.379