APOLIPOPROTEIN-B-CONTAINING PLASMA-LIPOPROTEINS IN HEALTH AND IN DISEASE

Coronary heart disease is declining slowly in many affluent nations, a lthough it remains their major cause of death and disability. In sharp contrast, many societies in Eastern Europe ave experiencing a substan tial 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 apol ipoprotein B (ape B) in the atherogenic process although apo-B-contai ning particles (very low density lipoproteins, low-density lipoprotein s, and chylomicrons) are essential for good health as shown by the gen etic 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 cove lipidation of apo B in the rough end oplasmic reticulum (RER). This discovery coincides with the articulati on of a novel concept called the two-step hypothesis of triglyceride-r ich particle assembly in hepatocytes and enterocytes forming very low density lipoproteins and chylomicrons, respectively. The first step is predicted to be dependent on MTP cove lipidating full-length apo B th at is firmly bound to the RER membrane. Core lipidation of apo B relea ses a small apo-B-rich particle from the RER membrane into the RER lum en. A larger triglyceride-rich but apo-B-deficient particle is formed independently in the smooth endoplasmic reticulum (SER). Usually, an a po-B-rich small particle formed in the RER coalesces with an apo-B-def icient larger particle from the SER as the second Step of assembly of nascent triglyceride-rich particles for secretion. In several conditio ns, small apo-B-rich particles formed in the first step in the RER are secreted directly into the blood, bypassing the second step. These ne w concepts of the mechanisms of origin of apo-B-containing plasma lipo proteins may soon facilitate dietary and pharmacologic interventions t hat lower blood levels of apo B, reducing the incidence of heart attac k and stroke.