Pathophysiology Lipid and Lipoprotein Metabolism

Cholesterol is an essential substance manufactured by most cells in the body. Cholesterol is used to maintain cell wall integrity and for the biosynthesis of bile acids and steroid hormones. Other major lipids in our body are triglycerides and phospholip-ids. Since cholesterol is a relatively water-insoluble molecule, it is unable to circulate through the blood alone. Cholesterol along with triglycerides and phospholipids are packaged in a large carrier-protein called a lipoprotein (Fig. 12-1). Lipoproteins are water soluble, which allows transportation of the major lipids in the blood. These lipoproteins are spherical and vary in size (approximately 1,000 to 6 nm) and density (less than 0.94 to 1.21 g/mL) (Table 12-1). The amount of cholesterol and triglycerides vary by lipoprotein size. The major lipoproteins in descending size and ascending density are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). When clinical laboratories measure and report serum total cholesterol, what they are measuring and reporting are the total cholesterol molecules in all the major lipoproteins. The estimated value of LDL cholesterol is found using the following equation:

LDL cholesterol = total cholesterol -(HDL cholesterol + triglyceridesP) using traditional units of mg/dL; or

LDL cholesterol = total cholesterol -(HDL cholesterol + triglycerides/2.2) using SI units of mmol/L.

If serum triglycerides are greater than 400 mg/dL (4.52 mmol/L), chylomicrons are present, or the patient has type III hyperlipoproteinemia, this formula becomes inac-

curate and LDL cholesterol must be directly measured.

Each lipoprotein has various proteins called apolipo-proteins (Apos) embedded on the surface (Fig. 12-1). These Apos serve four main purposes, they: (a) are required for assembly and secretion of lipoproteins (such as Apos B-48 and B-100); (b) serve as major structural components of lipoproteins; (c) act as ligands (Apo B-100 and Apo E) for binding to receptors on cell surfaces (LDL receptors); and (d) can be cofactors (such as Apo C-II) for activation of enzymes (such as lipoprotein lipase [LPL]) involved in the breakdown of triglycerides from chylomicrons and VLDL.4 Apos A-I and A-II are major structural proteins on the surface of HDL. Apo A-I interacts with adenosine triphosphate (ATP) binding cassette A1 and G1 to traffic cholesterol from extrahepatic tissue (such as the arterial wall) to immature or nascent HDL.

Cholesterol from the diet as well as from bile enters the small intestine, where it is emulsified by bile salts into micelles (Fig. 12-2). These micelles interact with the duodenal and jejunal enterocyte surfaces, and cholesterol is transported from the micelles into these cells by the Niemann-Pick Cl Like 1 (NPC1L1) transporter.5 Some cholesterol and most plant sterols, which are structurally similar to cholesterol, are exported back from the enterocyte into the intestinal lumen by the ATP-binding cassette (ABC) G5/G8 transporter. Cholesterol within enterocytes is esterified and packaged into chylomicrons along with triglycerides, phospholipids, and Apo B-48 as well as Apos C and E, which are then released into the lymphatic circulation. In the circulation, chylomicrons are converted to chylomicron remnants (through loss of triglycerides by the interaction of Apo C-II and LPL). During this process, chylomicrons also interact with HDL particles (Fig. 12-3) and exchange triglyceride and cholesterol content, and HDL particles acquire Apos A and C. Chylomicron remnant particles are then taken up by LDL-related protein (LRP).

Lipoprotein Structure

FIGURE 12-1. Lipoprotein structure. Lipoproteins are a diverse group of particles with varying size and density. They contain variable amounts of core cholesterol esters and triglycerides, and have varying numbers and types of surface apolipoproteins. The apolipoproteins function to direct the processing and removal of individual lipoprotein particles. (From LipoScience, Inc. with permission.)

FIGURE 12-1. Lipoprotein structure. Lipoproteins are a diverse group of particles with varying size and density. They contain variable amounts of core cholesterol esters and triglycerides, and have varying numbers and types of surface apolipoproteins. The apolipoproteins function to direct the processing and removal of individual lipoprotein particles. (From LipoScience, Inc. with permission.)

Table 12-1 Physical Characteristics of Lipoproteins

Composition 1%)

Lipoprotein

Density Ringe (g/mU

i ijtc (n ml

Chglnleitl

Triglycerides

A polip-i prptcin

thjfamtoiQ»

UK (twn (7,95

lm-uooo

Si-95

A-l, A-ILA-IV IH&C-lG^E

VLUL

Lt">i tKiri 1006

«■so

30-30

50-6S

B'100,0 IC-II Oll, E

I0L

1JOOG-I.OI9

25-iÜ

-10

20

6 100,1

LEU

1.019-IJ(»}

51-56

4-5

e-iw

HOL

1J063-1.21

6-10

2-7

A-L A-ILC-LOM.C-IHL

HOI. liK|h <Jrfr.ity Iqxifycttriiv l|)l. inCif nvfluU' c]cnr>ily lt;nlpriiCniT I IM. kw (JrmiEy li|xipi()1riri: VI tX.viTy lew cfcTr.ily IqK^iiolrin,

HOI. liK|h <Jrfr.ity Iqxifycttriiv l|)l. inCif nvfluU' c]cnr>ily lt;nlpriiCniT I IM. kw (JrmiEy li|xipi()1riri: VI tX.viTy lew cfcTr.ily IqK^iiolrin,

Pathophysiology Cholesterol

FIGURE 12-2. Intestinal cholesterol absorption and transport. Cholesterol from food and bile enter the gut lumen and are emulsified by bile acids into micelles. Micelles binding to the intestinal en-terocytes, and cholesterol and other sterols are transported from the micelles into the enterocytes by a sterol transporter. Triglycerides synthesized by absorbed fatty acids along with cholesterol and apoli-poprotein B-48 are incorporated into chylomicrons. Chylomicrons are released into the lymphatic circulation and are converted to chylomicron remnants (through loss of triglyceride), and then taken up by the hepatic LDL receptor-related protein (LRP). (ABC G5/G8, ATP-binding cassette G5/G8; Apo, apolipoprotein; CE, cholesterol ester; FA, fattyacid; NPC1L1, Niemann-PickCl Like 1;TG, triglyceride.)

FIGURE 12-2. Intestinal cholesterol absorption and transport. Cholesterol from food and bile enter the gut lumen and are emulsified by bile acids into micelles. Micelles binding to the intestinal en-terocytes, and cholesterol and other sterols are transported from the micelles into the enterocytes by a sterol transporter. Triglycerides synthesized by absorbed fatty acids along with cholesterol and apoli-poprotein B-48 are incorporated into chylomicrons. Chylomicrons are released into the lymphatic circulation and are converted to chylomicron remnants (through loss of triglyceride), and then taken up by the hepatic LDL receptor-related protein (LRP). (ABC G5/G8, ATP-binding cassette G5/G8; Apo, apolipoprotein; CE, cholesterol ester; FA, fattyacid; NPC1L1, Niemann-PickCl Like 1;TG, triglyceride.)

In the liver, cholesterol and triglycerides are incorporated into VLDL along with phospholipids and Apo B-100 (Fig. 12-4). VLDL particles are released into the circulation where they acquire Apo E and Apo C-II from HDL. VLDL loses its triglyceride content through the interaction with LPL to form VLDL remnant and IDL. IDL can be cleared from the circulation by hepatic LDL receptors or further converted to LDL (by further depletion of triglycerides) through the action of hepatic lipases (HL). Approximately 50% of IDL is converted to LDL. LDL particles are cleared from the circulation primarily by hepatic LDL receptors by interaction with Apo B-100. They can also be taken up by extrahepatic tissues or enter the arterial wall, contributing to atherogenesis.6

Cholesterol is transported from the arterial wall or other extrahepatic tissues back to the liver by HDL (Fig. 12-3). Apo A-I (derived from the intestine and liver) on nascent HDL interacts with ATP-binding cassette A1 (ABCA1) and Gl transporter on extrahepatic tissue. Cholesterol in nascent HDL is esterified by lecithin-cholesterol acyltransferase (LCAT) resulting in mature HDL. The esterified cholesterol can be transferred as noted above to Apo B-containing particles in exchange for triglycerides. Triglyceride-rich HDL is hydrolyzed by HL, generating fatty acids and nascent HDL particles, or the mature HDL can bind to the scavenger receptors (SR-BI) on hepatocytes and transfer their cholesterol ester content for excretion in the bile.

A variety of genetic mutations occur in the above steps during lipoprotein synthesis and metabolism that cause lipid disorders. The major genetic disorders and their effect on serum lipids are presented in Table 12-2. Disorders that increase serum cholesterol are generally those that affect the number or affinity ofLDL receptors (also known as Apo B-E receptors) known as familial hypercholesterolemia, or the ability of Apo B-100 to bind to the receptor known as familial defective Apo B-100. These patients commonly present with corneal arcus of the eye and xanthomas of extensor tendons of the hand and Achilles tendon. Elevations in triglycerides are generally associated with overproduction of VLDL, mutations in Apo E, or lack of LPL. Patients with extremely elevated serum triglycerides can develop pancreatitis and tuberoeruptive xanthomas. Most individuals have mild to moderate elevations in cholesterol caused by a polygenic disorder. Polygenic hypercholesterolemia is not as well understood as the single-gene disorders discussed above. Polygenic hypercholesterolemia is thought to be caused by various, more subtle genetic defects as well as environmental factors such as diet and lack of physical activity.

FIGURE 12-3. Reverse cholesterol transport. Cholesterol is transported from the arterial wall or other extrahepatic tissues back to the liver by HDL. Esterified cholesterol from HDL can be transferred to apolipoprotein B-containing particles in exchange for triglycerides. Cholesterol esters transferred from HDL to VLDL and LDL are taken up by hepatic LDL receptors or delivered back to extrahepatic tissue. (ABCA1, ATP-binding cassette A1; ABCG1, ATP-binding cassette G1; Apo, apolipoprotein; C, cholesterol; CE, cholesterol ester; CETP, cholesterol ester transfer protein; CM, chylomicrons; HDL, high-density lipoprotein; HL, hepatic lipase; LCAT, lecithin-cholesterol acyltransferase; LDL, low-density lipoprotein; SR-B1, scavenger receptors; TG, triglyceride; VLDL, very low-density lipoprotein.)

FIGURE 12-3. Reverse cholesterol transport. Cholesterol is transported from the arterial wall or other extrahepatic tissues back to the liver by HDL. Esterified cholesterol from HDL can be transferred to apolipoprotein B-containing particles in exchange for triglycerides. Cholesterol esters transferred from HDL to VLDL and LDL are taken up by hepatic LDL receptors or delivered back to extrahepatic tissue. (ABCA1, ATP-binding cassette A1; ABCG1, ATP-binding cassette G1; Apo, apolipoprotein; C, cholesterol; CE, cholesterol ester; CETP, cholesterol ester transfer protein; CM, chylomicrons; HDL, high-density lipoprotein; HL, hepatic lipase; LCAT, lecithin-cholesterol acyltransferase; LDL, low-density lipoprotein; SR-B1, scavenger receptors; TG, triglyceride; VLDL, very low-density lipoprotein.)

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