- Total serum cholesterol greater than 200 mg/dL.
- LDL cholesterol greater than 100 mg/dL.
- HDL cholesterol less than 40 mg/dL.
- Triglycerides greater than 150 mg/dL.
- Lipoprotein(a) less than 30 mg/dL.
Over the last decade, lipid screening has been established as a cornerstone of cardiac prevention in guidelines in primary care,
cardiology, and many other specialties. Statins, inhibitors of hydroxymethylglutaryl-coenzyme
A (HMG-CoA) reductase have become indispensable in the treatment of coronary artery disease (CAD) as well as in prevention of vascular
events in patients at high risk, such as those with diabetes mellitus.
Lipoproteins and Apolipoproteins
Esterified cholesterol and triglycerides are insoluble in blood and are transported in plasma by lipoproteins. These lipoproteins are known as high-density lipoprotein (HDL) cholesterol, low-density
lipoprotein (LDL) cholesterol, very-low density lipoproteins (VLDL),
intermediate-density lipoproteins (IDL), and chylomicrons (Figure 2–1). Lipoproteins carry
characteristic apolipoproteins in their outer layer that have functional
significance (apo A-I for HDL; apo B-100 for LDL, IDL, and VLDL;
and apo B-48 for chylomicrons). For example, apo B-100 is recognized
by the LDL receptor and is required for hepatic production and removal
of LDL. Other apolipoproteins, such as apo E and apo CI-CIII, have
long been known to play an important part in lipid metabolism, while the
effects of many apolipoproteins remain incompletely
The density and size-distribution of the major classes of lipoprotein particles. Lipoproteins are classified by density and size, which are inversely related. HDL, high-density lipoproteins;
IDL, intermediate-density lipoproteins; LDL, low-density lipoproteins;
VLDL, very low-density lipoproteins. (Reproduced, with permission,
from Rader DJ et al. Disorders of Lipoprotein Metabolism. In: AS
Fauci, E Braunwald, DL Kasper, SL Hauser, DL Longo, JL Jameson,
J Loscaizo (eds). Harrison’s Principles of Internal
Medicine, 17th edition. New York: McGraw-Hill; 2008.)
Traditionally, the lipoprotein metabolism has been separated into exogenous (ie, uptake of cholesterol and fat from food) and endogenous pathways (ie, metabolic turnover in plasma, liver, and bile) (Figure 2–2). These pathways represent
simultaneous events that are complementary. Key elements of dietary
fat and cholesterol metabolism, and metabolism of major lipoprotein
classes are discussed below.
The exogenous and endogenous lipoprotein metabolic pathways. The exogenous pathway transports dietary lipids to the periphery and the liver. The endogenous pathway transports hepatic lipids
to the periphery. FFA, free fatty acids; IDL, intermediate-density
lipoproteins; LDL, low-density lipoproteins; LDLR, low-density lipoprotein
receptor; LPL, lipoprotein lipase; VLDL, very low-density lipoproteins.
(Reproduced, with permission, from Rader DJ et al. In: AS Fauci, E Braunwald, DL Kasper, SL Hauser, DL Longo, JL Jameson, J Loscaizo (eds). Harrison’s Principles of Internal Medicine, 17th edition. New York: McGraw-Hill; 2008.)
Dietary fats are processed by pancreatic lipase to fatty acids to allow absorption across the intestinal epithelium, where they
are re-esterified to triglycerides. For further transport they form
large chylomicrons, lipoproteins that also carry esterified cholesterol,
apolipoprotein B-48, and apo CII (an apolipoprotein that acts as
an activator of lipoprotein lipase). Chylomicrons are secreted into
the lymphatic system, and eventually enter the bloodstream via the thoracic
duct. After hydrolysis by lipoprotein lipase, an enzyme present in the endothelium of many tissues, chylomicrons release fatty acids
into peripheral tissues to provide immediate energy for muscles
or to be stored as fat in adipose tissue. Similar to the intestinal
pathway of chylomicrons, VLDL serve as carriers to export triglycerides
from the liver and are also targets of lipoprotein lipase. After
chylomicrons and VLDL release most of their triglyceride content,
these smaller particles (called chylomicron remnant, and VLDL remnant
or IDL) contain a high core concentration of esterified cholesterol
and are considered by many clinicians to be of high atherogenic potential.
Chylomicron remnants and about half of VLDL remnants are then taken
up by the liver in an apo E mediated process for subsequent cholesterol metabolism,
while the remaining VLDL remnants act as the building block for LDL
Turnover of chylomicrons and VLDL is rapid, with VLDL carrying less than 30% of overall plasma triglycerides. Fasting
or zero-fat diets, therefore, lead to prompt improvement in acutely
elevated triglycerides in hypertriglyceridemia.
Absorption of dietary or recirculated biliary cholesterol is largely by diffusion across the intestinal brush border in the jejunum. It is important to recognize that only half of the intestinal cholesterol
is absorbed, mainly in the form of recirculated biliary cholesterol,
while less than 30% comes from dietary cholesterol. Dietary
plant sterols (phytosterols) or other sterols compete with cholesterol
uptake in this process and lead to cholesterol lowering by way of
reduced absorption. This explains why limiting the intake of dietary
cholesterol often shows only modest improvement in cholesterol levels. After
passive diffusion of cholesterol, the protein Nieman-Pick C1-like
1 (NPC1L1; inhibited by the drug ezetimibe) is critical in the uptake of sterols and cholesterol into intestinal enterocytes. In an active
process involving the adenosine triphosphate–binding cassette (ABC)-Transporter ABCG5/G8, sterols and cholesterol are largely transported back into the gut, while a small amount of free
cholesterol is esterified and transferred into chylomicrons for
subsequent hepatic uptake. In the liver, cholesterol is either incorporated
into VLDL or metabolized into bile acids. Cholesterol can also be
synthesized from acetyl-CoA, a process that is regulated by HMG-CoA and inhibited by statins.
LDL and HDL are continuously remodeled in plasma, a complex process involving enzymes, transfer proteins, and receptors. This allows LDL to act as a transporter of cholesterol from the liver to target
tissues, while HDL carries out the opposite function. Most enzymes
or proteins affect both classes and include hepatic lipase (HL),
cholesteryl-ester transfer protein ...