Therapeutic regulation of apoB100 metabolism in insulin resistance in vivo.
Elevated apolipoprotein (apo) B-100 is a common abnormality in insulin-resistant subjects with obesity and type 2 diabetes mellitus that increases risk of cardiovascular disease. ApoB-100 metabolism is complex. Kinetic studies using stable isotope tracer have provided useful mechanistic insight into its therapeutic regulation. Dysregulation of apoB-100 metabolism is integral to dyslipidaemia in the metabolic syndrome (MetS). This is dynamically related to a combination of overproduction of very-low density lipoprotein apoB-100 and decreased catabolism of apoB-containing particles, with accelerated catabolism of high-density lipoprotein (HDL) particles. These abnormalities may be consequent on a global effect of insulin resistance and accumulation of visceral and liver fat. Several therapeutic interventions, such as weight loss, physical exercise, statins, fibrates, fish oils and cholesteryl ester transfer protein inhibitors can correct apoB-100 metabolism in MetS. This encapsulates several kinetic mechanisms of action, including decreased secretion of apoB-100, increased catabolism of apoB-100 and delayed catabolism of HDL particles. Other agents, including cholesterol absorption inhibitors, niacins, and endocannabinoid-1 receptor blockers, have also been shown to improve plasma lipid and lipoprotein abnormalities in insulin resistance; their mechanisms of action require further investigation in MetS. The complementary mechanisms of action of different therapies support the use of combination regimens to treat dyslipoproteinaemia in MetS, including type 2 diabetes. Tracer methodology is a powerful tool to evaluate established and new lipid-regulating therapies.
Watts
Gerald F
GF
Metabolic Research Centre, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia. gerald.watts@uwa.edu.au
Ooi
Esther M M
EM
Chan
Dick C
DC
D000818:Animals; D053299:Apolipoprotein B-100 / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000209:etiology / Q000517:prevention & control; D008076:Cholesterol, HDL / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000503:physiopathology*; D006801:Humans; D007333:Insulin Resistance; D024821:Metabolic Syndrome / Q000503:physiopathology / Q000628:therapy; D009765:Obesity / Q000150:complications / Q000503:physiopathology; D012307:Risk Factors
D053299:Apolipoprotein B-100; D008076:Cholesterol, HDL