The three major pathways of
lipoprotein metabolism provide a superb paradigm to delineate systematically the familial
dyslipoproteinemias. Such understanding leads to improved diagnosis and treatment of patients. In the exogenous (intestinal) pathway, defects in LPL,
apoC-II,
APOA-V, and GPIHBP1 disrupt the catabolism of
chylomicrons and hepatic uptake of their remnants, producing very high TG. In the endogenous (hepatic) pathway, six disorders affect the activity of the LDLR and markedly increase
LDL. These include FH, FDB, ARH, PCSK9 gain-of-function mutations,
sitosterolemia and loss of
7 alpha hydroxylase. Hepatic overproduction of VLDL occurs in FCHL, hyperapoB,
LDL subclass pattern B, FDH and syndrome X, often due to
insulin resistance and resulting in high TG, elevated small
LDL particles and low HDL-C. Defects in
APOB-100 and loss-of-function mutations in PCSK9 are associated with low
LDL-C, decreased CVD and longevity. An absence of MTP leads to marked reduction in
chylomicrons and VLDL, causing
abetalipoproteinemia. In the reverse
cholesterol pathway, deletions or
nonsense mutations in
apoA-I or ABCA1 transporter disrupt the formation of the
nascent HDL particle. Mutations in LCAT disrupt esterification of
cholesterol in
nascent HDL by LCAT and
apoA-1, and formation of spherical HDL. Mutations in either CETP or SR-B1 and familial high HDL lead to increased large HDL particles, the effect of which on CVD is not resolved. The major goal is to prevent or ameliorate the major complications of many familial
dyslipoproteinemias, namely, premature CVD or
pancreatitis. Dietary and
drug treatment specific for each inherited disorder is reviewed.