Cytosolic triglycerides and oxidative stress in central obesity:: the missing link between excessive atherosclerosis, endothelial dysfunction, and β-cell failure?

被引:148
作者
Bakker, SJL
IJzerman, RG
Teerlink, T
Westerhoff, HV
Gans, ROB
Heine, RJ
机构
[1] Univ Groningen Hosp, Dept Internal Med, NL-9700 RB Groningen, Netherlands
[2] Free Univ Amsterdam Hosp, Res Inst Endocrinol Reprod & Metab, NL-1081 HV Amsterdam, Netherlands
[3] Vrije Univ Amsterdam, Dept Mol Cell Physiol, Amsterdam, Netherlands
关键词
insulin resistance; non-insulin-dependent diabetes mellitus; adenine nucleotide translocase; oxidative stress; free radicals; atherosclerosis; oxidative phosphorylation; obesity; endothelial dysfunction;
D O I
10.1016/S0021-9150(99)00329-9
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Central obesity is increasingly recognized as a risk factor for atherosclerosis and type 2 diabetes mellitus. Here we present a hypothesis that may explain the excess atherosclerosis, endothelial dysfunction and progressive beta-cell failure. Central obesity is associated with increased cytosolic triglyceride stores in non-adipose tissues such as muscles, liver and pancreatic beta-cells. A high cytosolic triglyceride content is accompanied by elevated concentrations of cytosolic long-chain acyl-CoA esters, the metabolically active form of fatty acids. These esters inhibit mitochondrial adenine nucleotide translocators, resulting in an intramitochondrial ADP deficiency. In vitro, such ADP deficiency is a potent stimulator of mitochondrial oxygen free radical production, and we assume that this mechanism is also active in vivo. The decline of organ function with normal ageing is thought to be due, at least partly, to a continuous low-grade mitochondrial oxygen free radical production. In tissues containing increased cytosolic triglyceride stores this process will be accelerated. Tissues with a high-energy demand or poor free radical scavenging capacity, such as pancreatic beta-cells, are likely to be more susceptible to this process. This is how we explain their gradual dysfunctioning in central obesity. Likewise we propose that the enhanced production of oxygen free radicals in endothelial cells, or Vascular smooth muscle cells, leads to the increased subendothelial oxidation of LDL and atherosclerosis, as well as to the endothelial dysfunction and microalbuminuria. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.
引用
收藏
页码:17 / 21
页数:5
相关论文
共 46 条
[1]   THE EFFECT OF THE PROTONMOTIVE FORCE ON THE REDOX STATE OF MITOCHONDRIAL CYTOCHROMES [J].
AZZONE, GF ;
SCHMEHL, I ;
CANTON, M ;
LUVISETTO, S .
BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS, 1994, 1187 (02) :140-144
[2]   PORTAL ADIPOSE-TISSUE AS A GENERATOR OF RISK-FACTORS FOR CARDIOVASCULAR-DISEASE AND DIABETES [J].
BJORNTORP, P .
ARTERIOSCLEROSIS, 1990, 10 (04) :493-496
[3]   CONTROL OF ELECTRON FLUX THROUGH THE RESPIRATORY-CHAIN IN MITOCHONDRIA AND CELLS [J].
BRAND, MD ;
MURPHY, MP .
BIOLOGICAL REVIEWS, 1987, 62 (02) :141-193
[4]   SUPEROXIDE AND HYDROGEN-PEROXIDE IN RELATION TO MAMMALIAN-CELL PROLIFERATION [J].
BURDON, RH .
FREE RADICAL BIOLOGY AND MEDICINE, 1995, 18 (04) :775-794
[5]   EFFECTS OF COENZYME A AND CARNITINE ON STEADY-STATE ATP-ADP RATIOS AND RATE OF LONG-CHAIN FREE FATTY-ACID OXIDATION IN LIVER-MITOCHONDRIA [J].
CHRISTIANSEN, EN ;
DAVIS, EJ .
BIOCHIMICA ET BIOPHYSICA ACTA, 1978, 502 (01) :17-28
[6]  
CHUA BH, 1977, J BIOL CHEM, V252, P6711
[7]   Islet amyloid polypeptide: Actions and role in the pathogenesis of diabetes [J].
Clark, A ;
Charge, SBP ;
Badman, MK ;
MacArthur, DA ;
deKoning, EJP .
BIOCHEMICAL SOCIETY TRANSACTIONS, 1996, 24 (02) :594-599
[8]  
COOK GA, 1987, J BIOL CHEM, V262, P2050
[9]  
ELAYAN IM, 1991, P SOC EXP BIOL MED, V198, P569
[10]   INCREASED LIPOLYTIC-ACTIVITY AND HIGH RATIO OF FREE FATTY-ACIDS TO ALBUMIN IN SERA FROM WOMEN WITH PREECLAMPSIA LEADS TO TRIGLYCERIDE ACCUMULATION IN CULTURED ENDOTHELIAL-CELLS [J].
ENDRESEN, MJ ;
LORENTZEN, B ;
HENRIKSEN, T .
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY, 1992, 167 (02) :440-447