Cytosolic triglycerides and oxidative stress in central obesity: the missing link between excessive atherosclerosis, endothelial dysfunction, and beta-cell failure?
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.
Bakker
S J
SJ
Research Institute for Endocrinology, Reproduction and Metabolism, University Hospital Vrije Universiteit, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. s.j.l.bakker@int.azg.nl
IJzerman
R G
RG
Teerlink
T
T
Westerhoff
H V
HV
Gans
R O
RO
Heine
R J
RJ
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology* / Q000503:physiopathology; D003600:Cytosol / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000503:physiopathology; D006801:Humans; D007515:Islets of Langerhans / Q000503:physiopathology*; D008954:Models, Biological; D009765:Obesity / Q000150:complications* / Q000378:metabolism; D018384:Oxidative Stress; D014280:Triglycerides / Q000378:metabolism*
D014280:Triglycerides