Rong Xiang1, Liang-Liang Fan1, Hao Huang1, Ya-Qin Chen2, Wanxia He3, Shuai Guo1, Jing-Jing Li1, Jie-Yuan Jin1, Ran Du1, Riqiang Yan3, Kun Xia1. 1. Department of Cell Biology, School of Life Sciences, Central South University, Changsha, China (R.X., L.-l.F., H.H., S.G., J.-J.L., J.-y.J., R.D., K.X.). 2. Department of Cardiology, Second Xiangya Hospital of Central South University, Changsha, China (Y.-q.C.). 3. Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, OH (W.H., R.Y.).
Abstract
BACKGROUND: Reticulon 3 (RTN3) is an endoplasmic reticulum protein that has previously been shown to play a role in neurodegenerative diseases, but little is known about its role in lipid metabolism. METHODS: Obese patients (n=149), hypertriglyceridemic patients (n=343), and healthy control subjects (n=84) were enrolled to assess their levels of RTN3. To explore the pathophysiological roles of RTN3 in the control of lipid metabolism, we used transgenic mice overexpressing the wild-type human RTN3 gene, the RTN3-null transgenic mouse model, and multiple Caenorhabditis legans strains for molecular characterization. The underlying mechanisms were studied with 3T3L1 cell cultures in vitro. RESULTS: We report that overexpressed RTN3 in mice induces obesity and higher accumulation of triglycerides. Increased RTN3 expression is also found in patients with obesity and hypertriglyceridemia. We reveal that RTN3 plays critical roles in regulating the biosynthesis and storage of triglycerides and in controlling lipid droplet expansion. Mechanistically, RTN3 regulates these events through its interactions with heat shock protein family A (Hsp70) member 5, and this enhanced interaction increases sterol regulatory element-binding protein 1c and AMP-activated kinase activity. CONCLUSIONS: This study provides evidence for a role of RTN3 in inducing obesity and triglyceride accumulation and suggests that inhibiting the expression of RTN3 in fat tissue may be a novel therapeutic approach to treat obesity and hypertriglyceridemia.
BACKGROUND:Reticulon 3 (RTN3) is an endoplasmic reticulum protein that has previously been shown to play a role in neurodegenerative diseases, but little is known about its role in lipid metabolism. METHODS:Obesepatients (n=149), hypertriglyceridemicpatients (n=343), and healthy control subjects (n=84) were enrolled to assess their levels of RTN3. To explore the pathophysiological roles of RTN3 in the control of lipid metabolism, we used transgenic mice overexpressing the wild-type humanRTN3 gene, the RTN3-null transgenicmouse model, and multiple Caenorhabditis legans strains for molecular characterization. The underlying mechanisms were studied with 3T3L1 cell cultures in vitro. RESULTS: We report that overexpressed RTN3 in mice induces obesity and higher accumulation of triglycerides. Increased RTN3 expression is also found in patients with obesity and hypertriglyceridemia. We reveal that RTN3 plays critical roles in regulating the biosynthesis and storage of triglycerides and in controlling lipid droplet expansion. Mechanistically, RTN3 regulates these events through its interactions with heat shock protein family A (Hsp70) member 5, and this enhanced interaction increases sterol regulatory element-binding protein 1c and AMP-activated kinase activity. CONCLUSIONS: This study provides evidence for a role of RTN3 in inducing obesity and triglyceride accumulation and suggests that inhibiting the expression of RTN3 in fat tissue may be a novel therapeutic approach to treat obesity and hypertriglyceridemia.
Authors: Shaobing O Zhang; Andrew C Box; Ningyi Xu; Johan Le Men; Jingyi Yu; Fengli Guo; Rhonda Trimble; Ho Yi Mak Journal: Proc Natl Acad Sci U S A Date: 2010-02-22 Impact factor: 11.205
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Authors: Frode Norheim; Karthickeyan Chella Krishnan; Thomas Bjellaas; Laurent Vergnes; Calvin Pan; Brian W Parks; Yonghong Meng; Jennifer Lang; James A Ward; Karen Reue; Margarete Mehrabian; Thomas E Gundersen; Miklós Péterfy; Knut T Dalen; Christian A Drevon; Simon T Hui; Aldons J Lusis; Marcus M Seldin Journal: Mol Syst Biol Date: 2021-01 Impact factor: 11.429