IMED1003 - Cholesterol Excretion and Summary (4)

Summary so Far

DIAGRAM ON SLIDE 3

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

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)

Cholesterol Homeostasis

DIAGRAM ON SLIDE 7

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

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

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

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

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

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

Excretion: Sitosterolaemia

- defective ABCG5/8

- elevated plasma, tissue cholesterol

- Xanthomas, premature cardiovascular disease

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

Summary

DIAGRAM ON SLIDE 16