title: Insulin resistance caused by lipotoxicity is related to oxidative stress and endoplasmic reticulum stress in LPL gene knockout heterozygous mice.
abstract: OBJECTIVE
  To investigate the correlation of hypertriglyceridemia with abnormal glucose metabolism and insulin resistance.
  
  
  METHODS
  Lipid and glucose metabolism, whole-body and tissue-specific insulin sensitivity, genes and proteins related with oxidative stress and endoplasmic reticulum (ER) stress were compared between LPL+/- and control mice at different weeks of age.
  
  
  RESULTS
  16-50-week LPL+/- mice had increased body weight compared with their respective controls. Fat mass in visceral adipose tissue (VAT) of 16 and 28-week LPL+/- mice were twice more than their control littermates, and 50-week LPL+/- mice showed the same trend of increase. Plasma lipids were higher in 16-50-week LPL+/- mice. 28- and 50-week LPL+/- mice had elevated tissue lipid accumulation (liver, skeletal muscle, pancreas) and impaired glucose tolerance, while 16-week LPL+/- mice showed no differences. Homeostasis model assessment of insulin resistance for 28 and 50-week LPL+/- mice were twofold greater, whereas that for 16-week LPL+/- mice had no change. Insulin-stimulated phosphorylated Akt (Ser473) in VAT of 28-week LPL+/- mice decreased by 80.6% (p = 0.001), and that in liver and skeletal muscle decreased by 62.4% (P < 0.001) and 51.8% (p = 0.005) respectively. Then we found that plasma malondialdehyde and reactive oxygen species levels in liver and skeletal muscle of LPL+/- mice were elevated. Increased ER stress biomarkers were also detected in liver and VAT of 28-week LPL+/- mice.
  
  
  CONCLUSIONS
  Systemic LPL deletion results in impaired glucose tolerance, whole-body and tissue-specific insulin resistance, which is associated with tissue lipid deposition in various insulin target tissues. Furthermore, the activation of oxidative stress and ER stress may play an important role in the development of tissue-specific and systemic insulin resistance.
authors: Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China. Electronic address: 1756366571@qq.com.
authors: Yang-Xue
authors: YX
authors: Li
authors: Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China. Electronic address: htt86226@163.com.
authors: Ting-Ting
authors: TT
authors: Han
authors: Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiaotong University, China. Electronic address: liuyangrj@126.com.
authors: Yang
authors: Y
authors: Liu
authors: Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China. Electronic address: alicezhe_2005@qq.com.
authors: Shuang
authors: S
authors: Zheng
authors: Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China. Electronic address: 475511243@qq.com.
authors: Yao
authors: Y
authors: Zhang
authors: Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China. Electronic address: sue_liuwei@163.com.
authors: Wei
authors: W
authors: Liu
authors: Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China. Electronic address: amin99@163.com.
authors: Yao-Min
authors: YM
authors: Hu
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001823:Body Composition; D059865:Endoplasmic Reticulum Stress; D005260:Female; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006579:Heterozygote; D006706:Homeostasis; D015228:Hypertriglyceridemia / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D015227:Lipid Peroxidation; D008071:Lipoprotein Lipase / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D007328:Insulin; D008071:Lipoprotein Lipase; D005947:Glucose
keywords: Endoplasmic reticulum stress; Insulin resistance; Lipoprotein lipase; Oxidative stress