A study of the mechanisms of methylglyoxal-induced changes in plasma lipid levels in Sprague-Dawley rats
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Dyslipidemia, defined as abnormal levels of plasma lipids, is an independent risk factor for cardiovascular diseases, and is increasing worldwide. Methylglyoxal (MG), a reactive glucose metabolite, is a causative factor for type 2 diabetes and is associated with hypertension. We have recently reported abnormal plasma lipid levels in Sprague-Dawley (SD) rats treated chronically with MG. The liver and the adipose tissue are the main organs that contribute to plasma lipid level regulation. The aim of this study was to explore the possible mechanism(s) of MG-induced dyslipidemia. MG (60 mg/kg/day) or 0.9% saline was administered to 12-week-old male SD rats by continuous infusion with a minipump for 28 days and thereafter, the liver, and the adipose tissue were isolated and the plasma was collected. We also used cultured 3T3-L1 adipocytes for molecular studies. We performed Oil-Red O staining and hematoxylin-eosin staining, ELISA, western blotting and quantitative PCR. In the liver of rats treated chronically with MG, there was increased protein expression of sterol regulatory element binding protein-2 (SREBP-2), 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and microsomal triacylglycerol transfer protein (MTP), with no change in SREBP-1 and low density lipoprotein (LDL) receptor. In the adipose tissue, MG treated rats showed enlarged abdominal adipocytes, and increased protein expression and/or mRNA of CCAAT-enhancer binding protein (C/EBP)α, C/EBPβ and tumor necrosis factor alpha (TNFα), with no significant change in peroxisome proliferator activated receptor gamma (PPARγ), adiponectin, leptin and lipoprotein lipase levels. The effects of MG were attenuated by aminoguanidine, a MG and an advanced glycation endproducts scavenger. The findings in adipose tissue were confirmed in cultured 3T3-L1 cells. Our results indicate that the increase in plasma cholesterol and triacylglycerols by MG may be due to increased activity of hepatic SREBP-2 and HMG-CoA reductase, and the subsequent increased cholesterol synthesis; and due to increased activity of MTP and the resultant increased VLDL synthesis. The increase in plasma free fatty acids may be due to increased triacylglycerol accumulation caused by over-expression of C/EBPα and C/EBPβ, increased adipocyte size and up-regulated gene expression of TNFα, and the resultant decreased free fatty acids uptake and increased lipolysis in adipocytes.
DegreeMaster of Science (M.Sc.)
SupervisorDesai, Kaushik; Wu, Lingyun
CommitteeRicharson, J.Steven; Liu, Lixin
Copyright DateOctober 2011