Elena Nikolaevna Pivovarova
Laboratory of Evolutionary Genetics, Institute of Cytology and Genetics SB RAS, Russia
It is known that the metabolic syndrome (MS) leads to serious cardiovascular disease which continues to be the number one cause of mortality in industrial countries. According to the National Cholesterol Education Program-Adult Treatment Panel III, the criteria of the metabolic syndrome include three or more impairments: increase in blood triglycerides, decrease in blood HDL cholesterol, hypertension, visceral obesity and increased blood glucose. The MS distribution is growing catastrophically, but molecular mechanisms responsible for development of complex impairments in MS still remain basically poorly investigated. A high percentage of MS morbidity determines much attention to MS modeling, mechanisms of MS development, and new approaches to MS treatment. The formation of complex MS symptoms suggests systemic impairments in lipid and carbohydrate metabolism; it appears that these impairments should have a common basis at the level of expression of appropriate genes. Expression of genes involved into lipid and carbohydrate metabolism is regulated by various transcription factors (TF), including peroxisome proliferator-activated receptors (PPAR) (Lefebvre P. et al., 2006], liver X receptors (LXR) (Herzog B. et al., 2007), pregnane X receptors (PXR), and constitutive androstane receptors (CAR) (Moreau A. et al., 2008). It has been previously shown that hypertension is accompanied by dyslipidemia and elevated levels of glucose in the blood in hypertensive ISIAH rats that can indicate a predisposition of this strain to the MC development. It was found that in ISIAH rats compared with normotensive WAG rats the signs of the metabolic syndrome are correlated with the altered functional activity of PPAR, LXR, PXR, and CAR involved in lipid and carbohydrate metabolism (Pivovarova Е. N. et all, 2011). Altered functional activity of these TF can suggest involvement of these TF in the development of MS in ISIAH rats. When modeling MS in laboratory animals fructose load often is used. It was shown that fructose load (10 % fructose in the drinking water for 10 weeks) leads to the increase in the level of triglycerides and glucose in the blood serum of ISIAH rats. It demonstrates relationship of high blood pressure, increased levels of glucose and increased levels of triglycerides. The endogenous ligands of PPAR are saturated fatty acids, native and oxidized unsaturated fatty acids, native and oxidized eicosanoids , prostaglandins, and prostacyclins. Ligands of LXR are oxidized cholesterol derivatives (oxysterols), whereas steroids and bile acids are endogenous ligands of PXR. PXR and CAR are mainly known as the sensors of xenobiotics. Since PPAR, LXR, PXR, and CAR are ligand-activated, they represent perspective targets for pharmacological treatments. In the recent time, the search of natural and synthetic PPAR ligands was in intensive process. There is a cross-talk between signal traducing pathways of PPAR, LXR, PXR, and CAR; this suggests their integrated role in regulation of genes of lipid and carbohydrate metabolism. Involvement of not only PPAR, but also LXR, PXR, and CAR in the development of MS suggests that their signal transduction pathways should be taken into consideration during design of pharmacological approaches.Complex studies of regulatory mechanisms, signaling pathways, and transcription targets for PPAR, LXR, PXR, and CAR may significantly help in better understanding of mechanisms of MS development and provide valuable information for development of appropriate pharmacological approaches to MS therapy.
Keywords: Metabolic syndrome, hypertension, dyslipidemia, glucose tolerance, and obesity, transcription factors PPAR, LXR, PXR, and CAR, hypertensive rat strain ISIAH.