Elizabeth P Newberry1, Zoe Hall2,3, Yan Xie1, Elizabeth A Molitor1, Peter O Bayguinov4, Gregory W Strout4, James A J Fitzpatrick4,5,6, Elizabeth M Brunt7, Julian L Griffin2,3, Nicholas O Davidson1. 1. Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. 2. Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom. 3. Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Biomolecular Medicine, Imperial College London, London, United Kingdom. 4. Washington University Center for Cellular Imaging, St. Louis, MO, USA. 5. Departments of Cell Biology & Physiology and Neuroscience, Washington University School of Medicine, St. Louis, MO, USA. 6. Department of Biomedical Engineering, Washington University in Saint Louis, St. Louis, MO, USA. 7. Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Abstract
BACKGROUND AND AIMS: Human transmembrane 6 superfamily 2 (TM6SF2) variant rs58542926 is associated with NAFLD and HCC. However, conflicting reports in germline Tm6sf2 knockout mice suggest no change or decreased very low density lipoprotein (VLDL) secretion and either unchanged or increased hepatic steatosis, with no increased fibrosis. We generated liver-specific Tm6Sf2 knockout mice (Tm6 LKO) to study VLDL secretion and the impact on development and progression of NAFLD. APPROACH AND RESULTS: Two independent lines of Tm6 LKO mice exhibited spontaneous hepatic steatosis. Targeted lipidomic analyses showed increased triglyceride species whose distribution and abundance phenocopied findings in mice with liver-specific deletion of microsomal triglyceride transfer protein. The VLDL triglyceride secretion was reduced with small, underlipidated particles and unchanged or increased apolipoprotein B. Liver-specific adeno-associated viral, serotype 8 (AAV8) rescue using either wild-type or mutant E167K-Tm6 reduced hepatic steatosis and improved VLDL secretion. The Tm6 LKO mice fed a high milk-fat diet for 3 weeks exhibited increased steatosis and fibrosis, and those phenotypes were further exacerbated when mice were fed fibrogenic, high fat/fructose diets for 20 weeks. In two models of HCC, either neonatal mice injected with streptozotocin (NASH/STAM) and high-fat fed or with diethylnitrosamine injection plus fibrogenic diet feeding, Tm6 LKO mice exhibited increased steatosis, greater tumor burden, and increased tumor area versus Tm6 flox controls. Additionally, diethylnitrosamine-injected and fibrogenic diet-fed Tm6 LKO mice administered wild-type Tm6 or E167K-mutant Tm6 AAV8 revealed significant tumor attenuation, with tumor burden inversely correlated with Tm6 protein levels. CONCLUSIONS: Liver-specific Tm6sf2 deletion impairs VLDL secretion, promoting hepatic steatosis, fibrosis, and accelerated development of HCC, which was mitigated with AAV8- mediated rescue.
BACKGROUND AND AIMS: Human transmembrane 6 superfamily 2 (TM6SF2) variant rs58542926 is associated with NAFLD and HCC. However, conflicting reports in germline Tm6sf2 knockout mice suggest no change or decreased very low density lipoprotein (VLDL) secretion and either unchanged or increased hepatic steatosis, with no increased fibrosis. We generated liver-specific Tm6Sf2 knockout mice (Tm6 LKO) to study VLDL secretion and the impact on development and progression of NAFLD. APPROACH AND RESULTS: Two independent lines of Tm6 LKO mice exhibited spontaneous hepatic steatosis. Targeted lipidomic analyses showed increased triglyceride species whose distribution and abundance phenocopied findings in mice with liver-specific deletion of microsomal triglyceride transfer protein. The VLDL triglyceride secretion was reduced with small, underlipidated particles and unchanged or increased apolipoprotein B. Liver-specific adeno-associated viral, serotype 8 (AAV8) rescue using either wild-type or mutant E167K-Tm6 reduced hepatic steatosis and improved VLDL secretion. The Tm6 LKO mice fed a high milk-fat diet for 3 weeks exhibited increased steatosis and fibrosis, and those phenotypes were further exacerbated when mice were fed fibrogenic, high fat/fructose diets for 20 weeks. In two models of HCC, either neonatal mice injected with streptozotocin (NASH/STAM) and high-fat fed or with diethylnitrosamine injection plus fibrogenic diet feeding, Tm6 LKO mice exhibited increased steatosis, greater tumor burden, and increased tumor area versus Tm6 flox controls. Additionally, diethylnitrosamine-injected and fibrogenic diet-fed Tm6 LKO mice administered wild-type Tm6 or E167K-mutant Tm6 AAV8 revealed significant tumor attenuation, with tumor burden inversely correlated with Tm6 protein levels. CONCLUSIONS: Liver-specific Tm6sf2 deletion impairs VLDL secretion, promoting hepatic steatosis, fibrosis, and accelerated development of HCC, which was mitigated with AAV8- mediated rescue.
Authors: Xiaobo Wang; Ze Zheng; Jorge Matias Caviglia; Kathleen E Corey; Tina M Herfel; Bishuang Cai; Ricard Masia; Raymond T Chung; Jay H Lefkowitch; Robert F Schwabe; Ira Tabas Journal: Cell Metab Date: 2016-10-27 Impact factor: 27.287
Authors: Yan Xie; Elizabeth P Newberry; Stephen G Young; Sylvie Robine; Robert L Hamilton; Jinny S Wong; Jianyang Luo; Susan Kennedy; Nicholas O Davidson Journal: J Biol Chem Date: 2005-12-13 Impact factor: 5.157
Authors: Oddgeir L Holmen; He Zhang; Yanbo Fan; Daniel H Hovelson; Ellen M Schmidt; Wei Zhou; Yanhong Guo; Ji Zhang; Arnulf Langhammer; Maja-Lisa Løchen; Santhi K Ganesh; Lars Vatten; Frank Skorpen; Håvard Dalen; Jifeng Zhang; Subramaniam Pennathur; Jin Chen; Carl Platou; Ellisiv B Mathiesen; Tom Wilsgaard; Inger Njølstad; Michael Boehnke; Y Eugene Chen; Gonçalo R Abecasis; Kristian Hveem; Cristen J Willer Journal: Nat Genet Date: 2014-03-16 Impact factor: 38.330
Authors: Xiaoxiao Jiang; Sam Fulte; Fengyan Deng; Shiyuan Chen; Yan Xie; Xiaojuan Chao; Xi C He; Yuxia Zhang; Tiangang Li; Feng Li; Colin McCoin; E Matthew Morris; John Thyfault; Wanqing Liu; Linheng Li; Nicholas O Davidson; Wen-Xing Ding; Hong-Min Ni Journal: J Hepatol Date: 2022-04-19 Impact factor: 30.083
Authors: Asmita Pant; Yue Chen; Annapurna Kuppa; Xiaomeng Du; Brian D Halligan; Elizabeth K Speliotes Journal: Int J Mol Sci Date: 2021-09-09 Impact factor: 5.923