Cardiovascular Disease research (focus: Statins and Glitazones)
LDL binds to endothelial cells and can be oxidised by free radicals generated by 'activated' endothelial cells to a lipid peroxide which can destroy the receptor needed for normal receptor-mediated removal of LDL from the plasma.
This modified LDL is taken up by scavenger receptors on macrophages (initiating atherosclerosis).
Lipoprotein (α) contains a unique apoprotein apo (α) which competes with and inhibits plasminogen. Plasminogen (+ plasminogen activator) generates the fibrinolytic enzyme - plasmin. It can also activate platelets (a thrombogenic effect)
Lipoproteins are classified into: High density lipoprotein, Low density lipoprotein, very low density lipoprotein and chylomicrons.
Statins are HMG-CoA reductase inhibitors, and affect circulating cholesterol concentrations (lipoprotein metabolism)
HMG-CoA is converted to mevalonate (which is later converted into cholesterol) via an intermediate which is imatated in the active form of the statin drug molecule. The drug molecule competitively binds the enzyme (HMG-CoA reductase) that does this transformation and therefore inhibits production of cholesterol.
HMG-CoA reductase is subject to feedback inhibition by diatry cholesterol, which supresses the synthesis of HMG-CoA synthase, HMG-CoA reductase and LDL receptors by binding to the DNA sequence of the promoter for the genes for all three of these products.
Lovastatin reduces cholesterol levels intracellularly, which increases production of all three. Increase in synthase and reductase are offset by the increase in LDL receptors on the cells.
The drug molecules are subject to extensive presystemic metabolism. Act in the liver
Overall: Decrease in cholesterol synthesis leads to an increase in synthesis of LDL receptors (removing LDL from the plasma)
Also reduce the hepatic production of VLDL, and therefore reduce plasma triglycerides and show a small increase in HDL cholesterol
PPAR (peroxisome proliferator activated receptor) transcription factors (αβγ) regulate gene expression of enzymes associated with lipid and glucose homeostasis and also promote the genesis of adipose tissue. PPAR (γ) is expressed preferably in fat cells and synergises with another transcription factor (C/EBPα) to convert precursor cells to fat ce1lls.
Thiazoladinediones bind to and activate PPAR (γ), allowing it to interacti with the retmoid X receptor, enhancing gene expression in areas controlling adipocyte differentiation, leading them to take up more fatty acids from the blood. Reduced availability of fatty acids to muscle improves insulin sensitivity. They 'enhance the response of tissue to insulin'.
They enhance glucose utilisation in peripheral tissues, especially adipocytes, and may also suppress gluconeogenesis in the liver by inhibition of the enzyme fructose-1,6-bisphosphatase.
+ can improve diabetic dyslipidaemia, decrease plasma triglycerides, increase HDL cholesterol (through lipolysis of VLDL),
- increase plasma LDL cholesterol and lipoprotein, obeisity through fat cell differentiation, fluid retention
Pharmacology, Rand et al. 4th Ed. Churchill Livingstone, 1999
Medical Pharmacology and Therapeurics, Waller et al. WB Saunders, 2001
Molecular Mechanisms of Drug Action, Coulson et al. 2nd Ed. Taylor & Francis, 1995