ABETALIPOPROTEINEMIA

What are Lipoproteins

Plasma Lipoproteins are spherical macromolecular complexes of lipids and specific proteins.

Function:
To

keep their component lipids soluble as they transport them in the plasma To provide an efficient mechanism for transporting their lipid contents to (and from) the tissues.

TYPES, COMPOSITION AND SYNTHESIS OF LIPOPROTEINS

CHYLOMICRONS

consist of triglycerides (85-92%), phospholipids (6-12%), cholesterol (1-3%) and proteins (1-2%) transport exogenous lipids to liver, adipose, cardiac, and skeletal muscle tissue

Stages of Chylomicrons
Nascent chylomicrons relatively large, having a diameter of 75 to 1,200 nm. are primarily composed of triglycerides (85%) and contain some cholesterol and cholesteryl esters. The main apolipoprotein component is apolipoprotein B-48 (apo B-48). Mature chylomicron While circulating in lymph and blood, chylomicrons exchange components with high-density lipoproteins (HDL). The HDL donates apolipoprotein C-II (APOC2) and apolipoprotein E (APOE) to the nascent chylomicron and thus converts it to a mature chylomicron (often referred to simply as "chylomicron"). APOC2 is the cofactor for lipoprotein lipase (LPL) activity. Chylomicron remnant Once triglyceride stores are distributed, the chylomicron returns APOC2 to the HDL (but keeps APOE), and, thus, becomes a chylomicron remnant, now only 3050 nm. APOB48 and APOE are important to identify the chylomicron remnant in the liver for endocytosis and breakdown.

VERY LOW DENSITY LIPOPROTEIN (VLDL)

type of lipoprotein made by the liver. enables fats and cholesterol to move within the bloodstream. is assembled in the liver from triglycerides, cholesterol, and apolipoproteins endogenous transport

LOW DENSITY LIPOPROTEIN (LDL)

enables transport of multiple different fat molecules, including cholesterol, within the water around cells and within the waterbased bloodstream Often referred to as the bad cholesterol

VLDL and LDL in the circulation

Release of VLDLs- VLDLs are secreted directly into the blood by the liver as nascent VLDL particles containing apolipoprotein B-100. They must obtain apo-C II and apo E from circulating HDL. Modification of Circulating VLDLs- as it passes through the circulation, TAG is degraded by lipoprotein lipase causing VLDL to decrease in size and become denser. C and E apoproteins are returned to HDL, but the particles retain apo B-100. Finally, triacylglycerols are transferred from VLDL to HDL in exchange reaction that concomitantly transfers cholesteryl esters from HDL to LDL. This exchange is accomplished by cholesteryl ester transfer protein. Production of LDL from VLDL in the plasma- with these modifications, the VLDL is converted in the plasma to LDL. An intermediate-sized particle or Intermediate Lipoprotein (remnant of VLDL) is observed during this transition. IDLs can also be taken up through receptor mediated endocytosis that uses apo E as the ligand.

HIGH DENSITY LIPOPROTEIN (LDL)

Enable lipids like cholesterol and triglycerides to be transported within the water-based bloodstream. Reservoir for apolipoproteins Reverse lipid transport Good Cholesterol

Reverse Lipid Transport

involves efflux of cholesterol from peripheral cells to HDL esterification of cholesterol to Phospahatidylcholine Cholesterol Transferase (PCAT/LCAT) binding of the cholesteryl ester rich HDL to liver and steroidogenic cells Selective transfer of CE into steroidogenic cells Release of lipid-depleted HDL

What are apolipoproteins? What is their significance?

Apolipoproteins are required for the assembly and structure of lipoproteins. Apolipoproteins also serve to activate enzymes important in lipoprotein metabolism and to mediate the binding of lipoproteins to cell-surface receptors.

Exogenous Transport

Exogenous Transport
1. 2. 3. 4. 5.

6.

Dietary cholesterol and fatty acids are absorbed. Triglycerides are formed in the intestinal cell from free fatty acids and glycerol and cholesterol is esterified. Triglycerides and cholesterol combine to form chylomicrons. Chylomicrons enter the circulation and travel to peripheral sites. In peripheral tissues, free fatty acids are released from the chylomicrons to be used as energy, converted to triglyceride or stored in adipose. Remnants are used in the formation of HDL.

Endogenous transport

Endogenous Transport
1. 2. 3. 4. 5. 6. 7. 8.

VLDL is formed in the liver from triglycerides and cholesterol esters. These can be hydrolyzed by lipoprotein lipase to form IDL or VLDL remnants. VLDL remnants are cleared from the circulation or incorporated into LDL. LDL particles contain a core of cholesterol esters and a smaller amount of triglyceride. LDL is internalized by hepatic and nonhepatic tissues. In the liver, LDL is converted into bile acids and secreted into the intestines. In non hepatic tissues, LDL is used in hormone production, cell membrane synthesis, or stored. LDL is also taken up by macrophages and other cells which can lead to excess accumulation and the formation of foam cells which are important in plaque formation.

ABETALIPOPROTEINEMIA

Define Abetalipoproteinemia What is the underlying genetic defect?

ABETALIPOPROTEINEMIA

an inherited disorder that affects the absorption of dietary fats, cholesterol, and fat-soluble vitamins Unable to synthesize beta lipoproteins (LDL) rare disorder with approximately 100 cases described worldwide. also known as Bassen-Kornzweig syndrome

MTTP gene provides instructions for making a protein called Microsomal Triglyceride Transfer Protein MTTP gene is located on the long (q) arm of chromosome 4 at position 24. Autosomal Recessive condition

Chromosome 4 at position 24

Why do the intestinal and hepatic cells accumulate fats in this disorder?

MTTP is linked for the apo B assembly. It loads apo B with lipid. significant interaction between MTTP and apo B lipoprotein for the synthesis of the apo B lipoproteins Apo B 48- synthesized in the intestinal mucosal cells Apo B 100- synthesized in the liver

ABETALIPOPROTEINEMIA
What

are its manifestations and possible complications? Why is Abetalipoproteinemia associated with fat-soluble vitamin deficiency?

ABETALIPOPROTEINEMIA
Why dont patients with this disorder develop vitamin D deficiency? Aside from abetalipoproteinemia, what other disoders may arise from derangements of lipoprotein functions? Discuss their genetic etiology and clinical manifestations.

Signs and Symptoms

Vomiting Fatty Diarrhea Abdominal distention Do not gain weight Growth retardation Mental retardation

Signs and Symptoms Sensory hypesthesia Movement chorea dysmetria dysarthria ataxia

Signs and Symptoms

Muscle weakness, shortening (contraction) of muscles in the back that causes the spine to curve (kyphoscoliosis)

Signs and Symptoms

Eye night blindness, poor eyesight, problems with eye control (ophthalmoplegia), cataracts

Signs and Symptoms

Blood low iron (anemia), problems with clotting, abnormal red blood cells (acanthocytosis)

Abetalipoproteinemia is associated with fat-soluble vitamin deficiency

Fat Soluble Vitamins

Require protein carriers to be transported in the blood Vitamin A, E, K normally transported from enterocytes to the liver by chylomicrons

Fat Soluble Vitamins

Inability

to make -lipoproteins causes severely reduced absorption/ malabsorption of dietary fats and fat soluble vitamins from the digestive tract to the bloodstream.

Why do patients with this disorder do not develop vitamin D deficiency?

Vitamin D is a fat soluble vitamin. In order to metabolize it, it is important that we have the specific lipoprotein apolipoprotein B in our bodies. Vitamin D deficiency is not present in abetalipoproteinemia since there are other sources aside from the dietary vitamin D.

Why do patients with this disorder do not develop vitamin D deficiency?

In addition, upon skin exposure to ultraviolet light, cutaneous provitamin D3 is converted to previtamin D3, which isomerizes into vitamin D3 and translocates into the circulation. So even in the presence of abetalipoproteinemia, Vitamin D can still be metabolized in our body.

Abetalipoproteinemia
Fat-soluble vitamins

Fats Chylomicron

Chylomicron formation (requires apolipoprotein B) - intestinal mucosa

Leave intestinal mucosa via lymphatic system

Vitamin A, E, K

circulation

Why dont patients with this disorder develop vitamin D deficiency?

Other disorders may arise from derangements of lipoprotein functions? Genetic etiology and clinical manifestations

Other disorders, etiology, manifestation

Lipoprotein Lipase & ApoC-II deficiency Genetic Etiology: LPL is required for the hydrolysis of triglycerides in chylomicrons and VLDL. ApoC-II is a cofactor for LPL Genetic deficiency of either LPL or apoCII results in impaired lipolysis and profound elevations in plasma chylomicrons.

Other disorders, etiology, manifestation

Lipoprotein Lipase & ApoC-II deficiency Manifestation: severe abdominal pain caused by acute pancreatitis retinal blood vessels are opalescent Eruptive xanthomas Hepatosplenomegaly

Other disorders, etiology, manifestation

FAMILIAL HYPERCHOLESTEROLEMIA Genetic Etiology: Low-density lipoprotein receptor gene (LDL); there are more than 100 known mutations. The LDL receptor recognizes apolipoprotein B100 or apolipoprotein E; therefore, a mutation of the receptor results in impaired uptake of cholesterol into cells.

Other disorders, etiology, manifestation

FAMILIAL HYPERCHOLESTEROLEMIA Manifestations Elevated cholesterol level: Heterozygotes have half the normal amount of LDL receptors and 2-3 times the normal level of cholesterol; homozygotes have ve or more times the normal level of cholesterol.

Other disorders, etiology, manifestation

FAMILIAL HYPERCHOLESTEROLEMIA Manifestations Tendon sheath xanthomas, corneal arcus, and xanthelasma. Early atherosclerosis and its consequences; homozygotes usuallydie of cardiovascular disease before the age of 30 years.

Other disorders, etiology, manifestation

APOA-I

DEFICIENCY

Genetic

Etiology: genetic deficiency of apoA-I due to deletion of apoA-1 gene results in the absence of HDL from the plasma

Other disorders, etiology, manifestation

APOA-I

DEFICIENCY

Manifestation:
Plasma

and tissue levels of free cholesterol are increased resulting in the development of corneal opacities and planar xanthomas. Premature CHD is generally seen in the apoA-1 deficient patients.