Much evidence now indicates that the b-adrenoceptor blockers induce proatherosclerotic serum lipid changes (increases in serum triglycerides, total cholesterol, and LDL cholesterol, and a reduction in HDL cholesterol) while alpha 1-adrenoceptor blockers produce an opposite antiatherosclerotic serum lip profile. The mechanisms involved in the dyslipidemic effects of the alpha- and beta-adrenoceptor blockers are poorly defined, but they most likely involve modification of the actions of circulating catecholamines on lipid metabolism. Alpha1- and Beta2-Adrenoceptor activation appears to influence hepatic fatty acid disposition and ketogenesis, but their physiological roles are unclear. The primary goal of this proposal is to investigate regulation of hepatic fatty acid metabolism and serum lipid by catecholamines and adrenoceptor blockers. The principal hypothesis of this study is that hepatic alpha1- adrenoceptor activation by catecholamines acts most importantly in inhibit fatty acid oxidation and promote triglyceride synthesis and secretion, and that beta-adrenoceptor stimulation produces the opposite effect. Previous in vitro liver studies of this subject have give widely conflicting results. Beta-Adrenoceptor activation is reported to modestly stimulate or have no effects on hepatic fatty acid oxidation, while alpha1-Adrenoceptor activation is reported to inhibit, have no effect or stimulate this process. These varying results may have been due to differences in study conditions and predominant use of mature male rate which have many hepatic alpha1-but only low number of Beta2-adrenoceptors. Female rats are a better animal model for such studies because like humans, their livers contain large numbers of both alpha1-and beta2- adrenoceptors. To test the primary hypothesis, adrenoceptor regulation of the metabolism of isotopic fatty acid in isolated hepatocytes from female rats will be investigated. Optimal conditions will be identified for eliciting Beta-adrenoceptor- mediated stimulation, and alpha1-adrenoceptor inhibition, of fatty acid oxidation in hepatocytes. The roles of the primary alpha1-adrenoceptor intracellular mediators, diacylglycerol (DAG), inositol trisphosphate (lP3) and Ca++, in alpha1-regulation of hepatocyte fatty acid oxidation will be characterize. Subsequent studies will determine if adrenoceptor effects on hepatic fatty acid disposition involve changes in fatty acid oxidation, esterification, or intracellular triglyceride lipolysis. In vivo experiments, epinephrine and other adrenergic agonists, and alpha1- and beta-adrenoceptor blockers, alone and in combination, will be administered chronically to rats, and levels of serum lipids will be determined. These experiments will characterize the influence of chronic hyperadrenergic states, such as occurs in stress, on atherosclerotic serum lipid changes. Results of these studies will provide important new information on the contributions of catecholamines and their receptor antagonists to atherosclerotic serum lipid changes.
| Wanic, Krzysztof; Placha, Grzegorz; Dunn, Jonathon et al. (2008) Exclusion of polymorphisms in carnosinase genes (CNDP1 and CNDP2) as a cause of diabetic nephropathy in type 1 diabetes: results of large case-control and follow-up studies. Diabetes 57:2547-51 |
