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Slide 10-7. Individuals with hereditary hypercholesterolemia make up less than 5% of all individuals with heart attacks, but hypercholesterolemia due to a gene-environment interaction is a very strong risk factor for heart disease. The data from the MRFIT trial shown here demonstrates that a cholesterol level of 240 mg/dl doubles the risk of heart attack compared to a cholesterol of 180 mg/dl. It is assumed that similar risk reduction occurs whether the cholesterol is reduced through diet or medication.

Slide 10-8. Obesity results in elevated insulin levels, which increase production of very low density lipoprotein particles which contain 80% triglycerides and 20% cholesterol. The obesity-induced overproduction of VLDL from the liver results in increased levels of VLDL remnans and LDL particles which are atherogenic. Saturated fat and and cholesterol reduce hepatic uptake of LDL particles further increasing the levels of circulating LDL cholesterol. Therefore, hypercholesterolemia is due to a genetic-environmental interaction with measurable effects of obesity, saturated fat and dietary cholesterol in susceptible individuals.

Slide 10-9. The balance between lipogenesis and lipolysis controlled by diet, hormones, and exercise have significant effects on lipid metabolism. Lipoprotein lipase synthesized in the fat cell is transported to the vessel wall where it breaks down triglycerides to glycerol and fatty acids. These are reassembled in the fat cell to be stored as triglycerides. Hormone-sensitive lipase then mediates the breakdown of stored triglycerides to fatty acids and glycerol. The fatty acids both recycle and are re-utilized for triglyceride synthesis, but the glycerol exits the fat cell without reuptake and is metabolized.

Slide 10-10. Exogenous and endogenous lipids are metabolized differently, but share common pathways. Dietary fat is taken up from the gut by chylomicrons, which are transported to the liver where they are metabolized and taken up in the pool for endogenous triglyceride synthesis. Endogenous triglycerides from the liver and chylomicrons carrying exogenous lipids are metabolized by lipoprotein lipase in muscle and fat cells.

Slide 10-11. At a cellular level, cholesterol biosynthesis is regulated by intracellular free cholesterol. When this pool is reduced, the number of receptors bringing cholesterol into the cell is increased and cholesterol biosynthesis is increased. When the intracellular cholesterol is increased, the number of receptors is decreased as is cholesterol biosynthesis. Dietary fiber, by binding cholesterol in the gastrointestinal tract and removing it from the body, reduces intracellular cholesterol and triggers an increase in cholesterol biosynthesis. Therefore, the observed reduction in total cholesterol due to dietary fiber is increased when it is given in combination with an inhibitor of cholesterol biosynthesis.

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