HORMONAL MODULATION OF LIPOPROTEIN METABOLISM

The water-insoluble lipids cholesterol and triglycerides are transported into the bloodstream by lipoproteins. These macromolecular complexes include several families, each of which plays specific roles in lipid transport. The functionality of this transport mechanism constitutes one of the major risk factors for the development of cardiovascular diseases. Pathologies such as obesity, insulin resistance, and type II diabetes, increase the risk of cardiovascular diseases partly because they bring about alterations in lipoprotein metabolism. These diseases are frequently associated with high levels of triglyceride-rich lipoproteins (VLDL), low levels of lipoproteins which transport cholesterol toward the liver (HDL, or ‘good cholesterol’), and high levels of cholesterol-rich lipoproteins (LDL, or ‘bad cholesterol’), the composition of which has been altered. Such a lipoprotein profile contributes to the development of cardiovascular diseases by favoring the formation of atheromatous plaques (atherosclerosis).

Our research program is focused on the study of alterations in lipid and lipoprotein metabolism which are associated with obesity, insulin resistance and diabetes, and on the modes of action of hormones which mediate these alterations. To this end, we use animal models (rat, mouse) which allow us to analyze the influence of hormones on lipid transport in a global physiological context, as well as in isolated cell systems (hepatocytes, adipocytes) for the study of their modes of action. Several hormones involved in the modulation of lipid metabolism are being investigated: insulin and glucocorticoids (their levels, efficiency and distribution in obesity, insulin resistance, and diabetes), catecholamines (the mediators of the sympathoadrenal system, which are increased by food intake and acute stress), leptin, a hormone secreted by adipose tissue that signals the brain on the status of fat storage in the body.

The experimental strategies used are the following:
•  modification of the hormonal status of normal animals, either by removal or addition of specific hormones in vivo;
• use of animal models of obesity, insulin resistance or diabetes of genetic or environmental (diet) origin;
• interventions (diet, energy expenditure, drugs) aimed at modifying the effects of such pathologies on lipid metabolism.

Evaluation of the impact of these interventions on lipid metabolism is carried out at several biological levels:
• hepatic synthesis and secretion of lipoproteins;
• intravascular metabolism of lipoproteins;
• genetic expression and cell biology of structural proteins (apo B, apo C-III) of lipoproteins;
• cell and intravascular biology of enzymes (lipoprotein lipase, hepatic lipase) which play a key role in lipoprotein metabolism;
• tissue uptake and intracellular metabolism of lipids (fatty acids, triglycerides).

Basic knowledge acquired through this research program contributes to the development of a better understanding and a more efficient control of lipoprotein metabolism. This knowledge will further enhance our ability to treat diseases that have become prevalent in industrialized societies.

These projects are supported by the Natural Sciences and Engineering Research Council of Canada, the Fonds FCAR, the Medical Research Council of Canada and the Canadian Diabetes Association.

Arvaniti K, Deshaies Y, Richard D The effect of leptin on energy balance does not require the presence of intact adrenals. American Journal of Physiology [Regulatory, Integrative, and Comparative Physiology], in press.