Pathogenesis of Atherogenic Dyslipidemia

Metabolic Origins of Atherogenic Dyslipidemia

One metabolic abnormality that is linked to atherogenic dyslipidemia is an accumulation of excess lipids in the liver.^[33,34,35] In many patients, lipid overload in the liver is manifest clinically by fatty liver. The hepatic accumulation of fat (triglyceride) appears to modify the liver's metabolism in a way that promotes the development of atherogenic dyslipidemia. Through mechanisms not yet determined, many of the factors regulating the formation and catabolism of lipoprotein appear to be increased in patients with fatty liver. A few examples are worth noting.

The presence of excess lipid in the liver promotes the incorporation of triglycerides into VLDL particles.^{[36,37,38,39]} This will lead to an enrichment of VLDL particles with triglycerides. But in addition, the number of VLDL particles secreted from the liver appears to be increased. The major apolipoprotein of VLDL particles is apo B-100. Normally, some apo B-100 is degraded in the liver and not used for formation of VLDL particles. Seemingly, when the liver contains excess lipids, more apo B-100 is recruited for the formation of VLDL particles, and consequently, more VLDL particles are secreted by the liver.^{[36,37,38,39]}

The consequences of an overproduction of VLDL particles with hepatic lipid overload are several. One response will be increases in plasma triglyceride and VLDL particles. This action contributes to a rise in VLDL remnants and, perhaps of equal importance, to an increase in the number of LDL particles.

This apolipoprotein, which probably is oversynthesized in patients with hepatic overload,^[40] interferes with the catabolism of TGRLP. Apo C-III has two actions. It impairs the action of lipoprotein lipase,^[41] and it retards the uptake of VLDL particles by the liver.^[42,43] Both actions lead to the retention of VLDL, especially VLDL remnants, in the circulation.

A key factor in the development of atherogenic dyslipidemia is an overactivity of hepatic lipase.^[44,45] This enzyme is located on endothelial cells of the liver and assists in hydrolysis of TGRLP. Perhaps more important, hepatic lipase degrades HDL particles. The low HDL-C level accompanying atherogenic dyslipidemia almost certainly is due in part to an overactivity of hepatic lipase. In the presence of obesity, which apparently leads to hepatic lipid overload, the synthesis of hepatic lipase is raised.^[46]

Hepatic lipid overload may lead to an increased synthesis of LDL receptors.^[47,48] However, this has not yet been proved.

Exactly how hepatic lipid overload stimulates the synthesis of lipoprotein regulators is not known. One possibility is that fatty acid oxidation is enhanced, which results in oversynthesis of lipoprotein metabolism regulators, as well as several of the coagulation factors. High plasma insulin levels, which are characteristic of patients with hepatic lipid overload,^[49,50,51] may be a factor driving the oversynthesis of lipoprotein regulators by the liver.

© 2000 Cliggott Publishing, Division of CMP Healthcare Media

Cite this: Pathogenesis of Atherogenic Dyslipidemia - Medscape - May 01, 2000.