Apolipoprotein-B-containing plasma lipoproteins in health and in disease

Coronary heart disease is declining slowly in many affluent nations, although it remains their major cause of death and disability. In sharp contrast, many societies in Eastern Europe are experiencing a substantial increase in atherosclerotic heart attack, possibly due largely to diets rich in saturated fat and cholesterol and to smoking. Most fats and cholesterol are transported in blood plasma in lipoproteins. Many studies implicate excessive blood levels of particles containing apolipoprotein B∗ (apo B) in the atherogenic process although apo-B-containing particles (very low density lipoproteins, low-density lipoproteins, and chylomicrons) are essential for good health as shown by the genetic disease of abetalipoproteinemia (abeta) in which these particles are absent. Recent research has identified a probable defect in abeta, the apparent absence of microsomal triglyceride transfer protein (MTP) that may be obligatory for core lipidation of apo B in the rough endoplasmic reticulum (RER). This discovery coincides with the articulation of a novel concept called the two-step hypothesis of triglyceride-rich particle assembly in hepatocytes and enterocytes forming very low density lipoproteins and chylomicrons, respectively. The first step is predicted to be dependent on MTP core lipidating full-length apo B that is firmly bound to the RER membrane. Core lipidation of apo B releases a small apo-B-rich particle from the RER membrane into the RER lumen. A larger triglyceride-rich but apo-B-deficient particle is formed independently in the smooth endoplasmic reticulum (SER). Usually, an apo-B-rich small particle formed in the RER coalesces with an apo-B-deficient larger particle from the SER as the second step of assembly of nascent triglyceride-rich particles for secretion. In several conditions, small apo-B-rich particles formed in the first step in the RER are secreted directly into the blood, bypassing the second step. These new concepts of the mechanisms of origin of apo-B-containing plasma lipoproteins may soon facilitate dietary and pharmacologic interventions that lower blood levels of apo B, reducing the incidence of heart attack and stroke.