IMED1003 - Cholesterol Excretion and Summary (4)

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13 Terms

1
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<p>Summary so Far</p>

Summary so Far

DIAGRAM ON SLIDE 3

<p>DIAGRAM ON SLIDE 3</p>
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<p>Enterohepatic circulation of bile acids: bile acids are reabsorbed</p>

Enterohepatic circulation of bile acids: bile acids are reabsorbed

- bile acids/bile salts secreted by gall bladder into small intestine

- these bile salts are Passively reabsorbed throughout digestive tract

- they can also be Actively reabsorbed in ilium (apical sodium-dependent bile salt transporter (ABST)

- these bile salts are Returned to liver via portal vein

- 95% bile acids are reabsorbed

- this whole process is called enterohepatic circulation of bile acids

<p>- bile acids/bile salts secreted by gall bladder into small intestine</p><p>- these bile salts are Passively reabsorbed throughout digestive tract</p><p>- they can also be Actively reabsorbed in ilium (apical sodium-dependent bile salt transporter (ABST)</p><p>- these bile salts are Returned to liver via portal vein</p><p>- 95% bile acids are reabsorbed</p><p></p><p>- this whole process is called enterohepatic circulation of bile acids</p>
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<p>Excretion of Free Cholesterol in Bile</p>

Excretion of Free Cholesterol in Bile

- major loss of cholesterol occurs through free excretion in bile

- Hepatocytes, enterocytes secrete excess free cholesterol directly into GI tract

- ABC transporters

- ABCG 5/8: apical side of enterocytes, hepatocytes

(basically bile moves from the blood into the small intestines)

<p>- major loss of cholesterol occurs through free excretion in bile</p><p>- Hepatocytes, enterocytes secrete excess free cholesterol directly into GI tract</p><p>- ABC transporters</p><p>- ABCG 5/8: apical side of enterocytes, hepatocytes</p><p></p><p>(basically bile moves from the blood into the small intestines)</p>
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<p>Cholesterol Homeostasis</p>

Cholesterol Homeostasis

DIAGRAM ON SLIDE 7

<p>DIAGRAM ON SLIDE 7</p>
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<p>Cellular Regulation of Cholesterol: Points of Control</p>

Cellular Regulation of Cholesterol: Points of Control

SYNTHESIS:

- HMG-CoA reductase:

- Post transcriptional modification

- transcriptional modification

- Proteolytic degredation

STORAGE:

- Cholesterol acetyltransferase (ACAT)

UPTAKE:

- Transcriptional regulation of LDL receptor

.

THIS NEXT THING IS FOR SYNTHESIS:

- when cholesterol levels are high, protein is tagged for degredation and proteolysis which means we dont have synthesis of cholesterol

- when intracellular levels of cholesteorl are low, HMG-CoA transcription is upregulated, whcih means we produce more of the enzyme

<p>SYNTHESIS:</p><p>- HMG-CoA reductase:</p><p>- Post transcriptional modification</p><p>- transcriptional modification</p><p>- Proteolytic degredation</p><p>STORAGE:</p><p>- Cholesterol acetyltransferase (ACAT)</p><p>UPTAKE:</p><p>- Transcriptional regulation of LDL receptor</p><p>.</p><p>THIS NEXT THING IS FOR SYNTHESIS:</p><p>- when cholesterol levels are high, protein is tagged for degredation and proteolysis which means we dont have synthesis of cholesterol</p><p>- when intracellular levels of cholesteorl are low, HMG-CoA transcription is upregulated, whcih means we produce more of the enzyme</p>
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Genetic Disorders caused by disrupted cholesterol homeostasis

- genetic disorders: genes encoding metabolic enzymes, transporters, receptors required for cholesterol

- Synthesis

- Absorption

- Distribution (reverse cholesterol transport)

- Distribution (endogenous cholesterol transport pathway)

- Excretion

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Synthesis: Smith-Lemli-Opitz Syndrome

- cholesterol is required for signalling in embryonic development (establish positions of specialised cells, tissues, organs)

- Cholesterol availability: limiting prerequisite for myelin synthesis

- Brain: 20-25% cholesterol by mass

- Lipoproteins in blood cannot deliver cholesterol due to blood brain barrier

- Cholesterol synthesis crucial for CNS development

- Malformations of heart and kidney, cleft palate, mental and growth retardation

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<p>Absorption: Abetalipoporteinemia</p>

Absorption: Abetalipoporteinemia

- defective microsomal triglyceride transport protein (MTP)

- required for formation of CM (chylomicron) in enterocytes, VLDL in hepatocytes

- unable to absorb lipids, fat-soluble vitamins

- Severe deficiency in fat-soluble vitamins

- very rare

<p>- defective microsomal triglyceride transport protein (MTP)</p><p>- required for formation of CM (chylomicron) in enterocytes, VLDL in hepatocytes</p><p>- unable to absorb lipids, fat-soluble vitamins</p><p>- Severe deficiency in fat-soluble vitamins</p><p>- very rare</p>
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<p>Reverse Cholesterol Transport: Tangier Disease</p>

Reverse Cholesterol Transport: Tangier Disease

- defective ABCA1

- cholesterol can not be exported by many cells, including macropahges

- failure of reverse cholesterol transport leads

- severe and early cardiovascular diseases

.

Defective ABCA1 inhibits reverse cholesterol transport because it is the primary transporter responsible for moving cholesterol and phospholipids from inside cells, particularly macrophages, to the exterior. Without a functional ABCA1 transporter, cholesterol accumulates in the cell, preventing it from being loaded onto high-density lipoproteins (HDL) for transport back to the liver, which stops the reverse cholesterol transport pathway at its initial and rate-limiting step.

<p>- defective ABCA1</p><p>- cholesterol can not be exported by many cells, including macropahges</p><p>- failure of reverse cholesterol transport leads</p><p>- severe and early cardiovascular diseases</p><p>.</p><p>Defective ABCA1 inhibits reverse cholesterol transport because it is the primary transporter responsible for moving cholesterol and phospholipids from inside cells, particularly macrophages, to the exterior. Without a functional ABCA1 transporter, cholesterol accumulates in the cell, preventing it from being loaded onto high-density lipoproteins (HDL) for transport back to the liver, which stops the reverse cholesterol transport pathway at its initial and rate-limiting step. </p><p></p>
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<p>Endogenous Cholesterol Distribution: Familial Hypercholesterolemia</p>

Endogenous Cholesterol Distribution: Familial Hypercholesterolemia

- defective LDL receptor

- LDL can not be absorbed by extrahepatic tissues or liver

- LDL accumulates

- [LDL] in plasma increases

- Early development of CVD

<p>- defective LDL receptor</p><p>- LDL can not be absorbed by extrahepatic tissues or liver</p><p>- LDL accumulates</p><p>- [LDL] in plasma increases</p><p>- Early development of CVD</p>
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<p>Excretion: Sitosterolaemia</p>

Excretion: Sitosterolaemia

- defective ABCG5/8

- elevated plasma, tissue cholesterol

- Xanthomas, premature cardiovascular disease

<p>- defective ABCG5/8</p><p>- elevated plasma, tissue cholesterol</p><p>- Xanthomas, premature cardiovascular disease</p>
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<p>Excess plasma cholesterol causes cardiovascular disease</p>

Excess plasma cholesterol causes cardiovascular disease

- Ratio of LDL:HDL essential for effective reverse cholesterol transport

- Cholesterol blood test: monitors concentrations of these lipoproteins

- Dietary absorption of cholesterol itself is poor, however some dietary patterns increase LDL

- LDL exceeds needs of tissues, overwhelms capacity for cholesterol scavenging by HDL

- Major cause of cardiovascular disease

- Pharmacological management - inhibit HMG CoA reductase with statins

.

- remember that HMG-CoA endogenously synthesises. We are limiting its natural syntrhesis becuase our diet has too much

<p>- Ratio of LDL:HDL essential for effective reverse cholesterol transport</p><p>- Cholesterol blood test: monitors concentrations of these lipoproteins</p><p>- Dietary absorption of cholesterol itself is poor, however some dietary patterns increase LDL</p><p>- LDL exceeds needs of tissues, overwhelms capacity for cholesterol scavenging by HDL</p><p>- Major cause of cardiovascular disease</p><p>- Pharmacological management - inhibit HMG CoA reductase with statins</p><p>.</p><p>- remember that HMG-CoA endogenously synthesises. We are limiting its natural syntrhesis becuase our diet has too much</p>
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<p>Summary</p>

Summary

DIAGRAM ON SLIDE 16

<p>DIAGRAM ON SLIDE 16</p>