Lipoprotein Metabolism, Cardiovascular Disease and Obesity

Question 1

3 features of atherosclerotic lesions

Answer 1

Fibrous cap Foam cells (macrophages full of cholesteryl ester) Necrotic core (full of cholesterol crystals)

Question 2

4 examples of plasma lipoproteins from biggest to smallest

Answer 2

Chylomicrons VLDLs (both rich in triglycerides) LDLs (main cholesterol carriers) HDLs (HDL2 > HDL3)

Question 3

Which lipoprotein is cholesterol stored in the most

Answer 3

LDLs

Question 4

Which lipoprotein is important after a meal?

Answer 4

Chylomicrons important in cholesterol transport after a meal Their cholesterol content in fasted state is very small

Question 5

Cholesterol absorption

Answer 5

Cholesterol entering the intestines comes from two sources: the diet and the bile

Most of the cholesterol coming down into the upper small intestine is derived from the bile duct

Cholesterol is then solubilised within mixed micelles (in which the major components are bile acids)

It is then transported across the intestinal epithelial brush border by NPC1L1

• Main determinant of cholesterol transport going into the lymphatics, and then to the liver

There are two transporters (ABC G5, ABC G8) that transport cholesterol back into the intestinal lumen

The balance between these three transporters determines the net amount of cholesterol absorbed

Question 6

Where are bile acids reabsorbed?

Answer 6

Bile acids will travel all the way down to the terminal ileum before being reabsorbed.

Question 7

Cholesterol metabolism in the liver: HMG CoA reductase

Answer 7

On arrival at the liver, cholesterol downregulates the activity of HMG CoA reductase. HMG CoA reductase is main enzyme involved in cholesterol synthesis from acetate and mevalonic acid. Therefore, the amount of cholesterol synthesised in the liver depends on the amount of cholesterol absorbed at the intestine.

People who are efficient at absorbing cholesterol have low rates of cholesterol synthesis, and vice versa.

Question 8

the two fates of cholesterol in the liver

Answer 8

Hydroxylation by 7-hydroxylase into bile acids

• The bile acids will then be excreted via the bile ducts.

Esterified by ACAT enzyme to produce cholesterol esters

• Together with triglycerides and ApoB, cholesterol esters are incorporated into VLDL particles (which involves the MTP transfer protein).

Question 9

Cholesterol packaging in the liver (MTP, VLDL/LDL/LDLr)

Answer 9

MTP packages cholesteryl ester to VLDL

LDLs transport cholesterol from the liver to the periphery to cells that have LDL receptors

• VLDL is the main precursor of LDL
• After circulation in the plasma for 3-4 days, LDLs are taken up by the liver via LDL surface receptors

Question 10

What is the role of HDL

Answer 10

HDLs pick up excess cholesterol from the periphery (involves ABC A1, which mediates the movement of free cholesterol from the peripheral cells to the HDL).

Question 11

What is the role of CETP (cholesteryl ester transport protein)?

Answer 11

CETP mediates the movement of:

• Cholesterol ester from HDL to VLDL
• Triglyceride from VLDL to HDL

Following this process, some of the HDL cholesterol ester is taken up by the liver via an SR-B1 receptor.

Question 12

Trigylyceride transport: chylomicrons and VLDL

Answer 12

VLDL = major triglyceride transporter in fasting state, it is endogenously synthesised (from the liver)

fasting state = little triglyceride in chylomicrons, have short life-span so following a fatty meal, there will be a peak in chylomicrons, but then they rapidly disappear

Question 13

triglycerides -> chylomicrons

Answer 13

Triglycerides are hydrolysed into fatty acids

They are then re-synthesised into triglycerides

These resulting triglycerides are transported via chylomicrons into the plasma

Question 14

What happens to chylomicrons containing triglycerides?

Answer 14

Chylomicrons are then hydrolysed into free fatty acids (FFA) by lipoprotein lipase enzyme (present in capillaries, particularly in relation to muscles). These free fatty acids are partly taken up by the liver and partly taken up by adipose tissue.The liver resynthesises these free fatty acids into triglycerides and packages them into VLDLs. VLDLs will also be acted upon by lipoprotein lipase to liberate the free fatty acids.

Question 15

What are the 4 main dyslipidaemias?

Answer 15

Hypercholesterolaemias

Hypertriglyceridaemias

Mixed hyperlipidaemia

Hypolipidaemias

Question 16

What is the cause of primary hypercholesterolaemia

Answer 16

NOT SECONDARY to any other disorder

usually implies a GENETIC bases

most important to consider is familial hypercholestolaemia

Question 17

Familial hypercholesterolaemi (type II)

Which genes

Answer 17

Increases risk of premature coronary disease by 5-10%

Dominant mutations of:

• LDL receptor
• ApoB gene (major protien in LDL)
• PCSK9

Recessive very rare = LDLRAP1

Question 18

Clinical feature of familial hypercholesterolaemia

Answer 18

Homozygous = corenal arcus

Heterozygous (common)

• corneal arcus
• xanthelasma
• tendon xanthomata (achilles tendon is thickened and roughened)

Question 19

Atheroma of aortic root in familial hypercholesterolaemia homozygote

Answer 19

atherosclerosis affecting aortic root

impinges on coronary ostia (entries into coronary arteries)

these patients would pass away in teenage years due to coronary infsufficiency

Question 20

LDL receptor function (in what cases is FH more severe)

Answer 20

The phenotype of the mutation will depend on which part of the LDL receptor is affected by the mutation (e.g. if there is a large mutation in the ligand-binding region of the receptor, the disease will be more severe.

Question 21

PCSK9 mutation (FH)

Answer 21

chaperone protein = bind to LDLr to promote its degradation

gain of function mutation in FH -> increased breakdown of LDLr -> high LDL levels

Question 22

Other types of primary hypercholesterolaemias

Answer 22

Polygenic hypercholesterolaemia:

• another form of primary hypercholesterolaemia that is caused by multiple gene mutations (NPC1L1, HMGCR and CYP7A1)

Familial hyperalphalipoproteinaemia:

• an increase in HDL which is caused by deficiency of CETP:
• relatively beign
• risk of premature coronary disease is not as pertinent – this is associated with longevity

Phytosterolaemia:

• a disease in which plasma concentrations of plant sterols are increased (namely sitosterol and campesterol). It is due to mutations in ABC G5 and ABC G8
• rare
• the main function of ABC G5 and ABC G8 is to prevent the absorption of plant sterols
• premature atherosclerosis is very common in this condition – plant sterols are just as atherogenic, if not more so, than cholesterol itself

Question 23

Primary hypertrigyleridaemia: Familial Type I

cause

mechanism

test tube

what sign can you see in some patients

Answer 23

deficiency in LPL/ApoC II (activates LPL)

LPL degrades CM

refrigerate overnight -> CM layer

eruptive xanthomatosis: when very high cholesterol/lipids. Firm, yellow, waxy, pea-like bumps on the skin are surrounded by red halos and are itchy

Question 24

Primary hypertriglyceridaemia: Familial Type IV and V

mx for Type I, IV and V

Answer 24

Familial Type IV: caused by increased synthesis of triglycerides

• The cause is unknown
• This test tube shows whole blood – there are no chylomicrons here
• The white substance is primarily VLDL (chylomicrons can float to the top, whereas VLDLs don’t)

Familial Type V: due to deficiency of ApoA V

• This is a more severe version of Type IV
• After overnight standing, there is a mixture of chylomicrons and VLDL
• Chylomicrons have floated to the top

Mx: reduce uptake of fat (diet)

Question 25

Primary mixed hyperlipidaemia: familial dysbetalipoproteinaemia (type III) what gene signs

Answer 25

rare aberrate form of ApoE 2/2 (normal type is ApoE 3/3) = homozygous phenotype **yellowing of the palmar crease** (palmar striae) and **eruptive xanthomas** on elbows

Question 26

Other primary mixed hyperlipidaemias

Answer 26

**Familial combined hyperlipidaemia** * Some people in the family will have high cholesterol and other will have high triglycerides (it is uncertain why this happens). **Familial hepatic lipase deficiency** * Another type of mixed hyperlipidaemia.

Question 27

Secondary hyperlipidaemia causes

Answer 27

**Pregnancy** * In pregnancy, there is always an increase in lipoproteins. A patient with the _Type I Primary Hypertriglyceridaemia_ (lipoprotein lipase deficiency) and then fall pregnant, this can become a major problem (may lead to pancreatitis and infant/maternal death). **Exogenous sex-hormones** * These can cause increases in lipoproteins (particularly, _oestrogen-containing compounds_ cause an increase in triglycerides). **Diabetes** * Diabetes is often associated with hypertriglyceridaemia (as with all the other metabolic secondary causes in the table). Diabetic patients may have eruptive xanthomas all over their bodies. Another metabolic disorder associated with hypertriglyceridaemia is progressive partial lipodystrophy. **Nephrotic syndrome (CHOLESTEROLAEMIA)** * The loss of protein in the urine in combination with a low serum albumin _activates LDL synthesis -\> very high cholesterol level_s in the nephrotic syndrome. If you ever have a patient with a markedly increased cholesterol, _check the urine protein content._ **Chronic renal failure, on dialysis or post-transplant** * This gives rise to triglyceride disorders. **Obstructive liver disease (CHOLESTEROLAEMIA)** * This can give rise to a particular form of hypercholesterolaemia. Primary biliary cirrhosis can give rise to xanthelasmas. **Excess alcohol consumption** * Alcohol consumption in excess is a very common cause of hypertriglyceridaemia.

Question 28

4 types of hypolipidaemias

Answer 28

_A-lipoproteinaemia (LDL/VLDL)_ * A rare, autosomal recessive disorder * The patient has extremely **low levels of cholesterol** (particularly LDL and VLDL cholesterol) * This is due to an **inherited deficiency of MTP** (microsomal triglyceride transfer protein) _Hypo-lipoproteinaemia (LDL)_ * An autosomal dominant disease involving **mutations of the ApoB gene -\> truncated ApoB protein** * Causes **low levels of LDL** Tangier Disease (HDL) * Tangier disease involves an **HDL deficiency** * Caused by mutations in **ABC A1** (mediates movement of cholesterol from peripheral cells into HDL) Hypoa-lipoproteinaemia * Sometimes caused by mutation of ApoA1

Question 29

Atherosclerosis = LDL mechanism

Answer 29

Atherosclerosis is particularly associated with increases in LDL (other risk factors too) The LDL becomes oxidised once it has penetrated the vascular wall Once oxidised, it gets taken up by macrophages Inside the macrophages, the cholesterol within the LDLs becomes esterified à foam cells The cholesterol in the arterial wall is often separated from the lumen by a thin, fibrous cap. This cap can easily rupture under some abnormal stress (e.g. intense exercise). This results in a thrombus.

Question 30

3 fates of a thrombis

Answer 30

Heal * When the fissure heals, the thrombus is ‘buried’ and this increases the overall size of the plaque. Become a mural thrombus * A mural intraluminal thrombus/intraintimal thrombus does not fully occlude the artery, but partially occludes it. Become an occlusive thrombus * This will block the artery and give rise to a myocardial infarct.

Question 31

Lipid regulating drugs (5)

Answer 31

**Statins** (e.g. atorvastatin) are the main way of reducing LDL cholesterol * Up to a 50% reduction with a decent dose of an appropriate statin * Slight increase in HDL and modest decrease in triglycerides * Statins have been around since 1989 * They reduce total and coronary mortality by 12% and 19% respectively * They reduce major vascular events by 25% for every 1 mmol/l reduction in LDL cholesterol * A large part of the 50% reduction in CVS mortality in England can be put down to statins **Nicotinic acid** showed potential as it causes a significant increase in HDL * Lowers LDL slightly, increases HDL significantly and reduces triglycerides * However, it has now been removed from the market due to its side-effect profile **Fibrates (e.g. gemfibrozil)** are not brilliant at modifying levels of LDL or HDL * However, they are very good at lowering triglycerides **Ezetimibe** is a cholesterol absorption blocker (blocks NPC1L1) * doesn’t have much of an effect on HDL and LDL levels **Colestyramine** is an anion-exchange resin that binds to bile acids and reduces their absorption * Bile acids cannot be reabsorbed, and the liver sense this * The liver produces more bile acids (which are made from cholesterol) * This stimulates cholesterol catabolism, and an overall reduction in circulating LDLs

Question 32

Lipoprotein A importance

Answer 32

**Lipoprotein A** * large lipoprotein made by the liver. * it is a **cardiovascular risk factor** * should be measured once **(using isoform insensitive assay)** in subjects at intermediate/high CVD/CHD risk, including FH, or with premature/statin-resistance CVD). * a desirable level of lipoprotein A is **\<500 mg/L.** * treatment should primarily be **nicotinic acid, 1-3 g/day**. In refractory cases, **weekly LDL-apheresis** is effective.

Question 33

Treatment of obesity

Answer 33

**Hypocaloric diet and exercise** (require willpower and commitment) Iatrogenic malabsorption **(Orlistat 120 – 360 mg daily)** * NOTE: this is a _pancreatic lipase inhibitor_ * Fat is not hydrolysed -\> passes through the digestive system unabsorbed * Consequence: steatorrhea **Bariatric surgery** (if BMI \> 40)

Question 34

Major forms of bariatric surgery (3)

Answer 34

**Gastric banding** * The size of the stomach is reduced using a band; the patient feels full even after a small meal **Roux- en-Y gastric bypass** * The upper jejunum is sectioned, and the distal part of the jejunum is anastomosed to the stomach. A portion of the jejunum is no longer absorbing anything, because the bile acids and pancreatic enzymes mediating absorption of lipid are introduced lower down in the tract. **Biliopancreatic diversion** * A reduced size in the stomach, much of the jejunum that is no longer in circuit. There is a lot of jejunum that is no longer doing anything (so for this portion of the intestine, nothing is being reabsorbed). A connection is made straight from the stomach to the terminal ileum, at which point absorption can take place.

Question 35

Benefits and risks of bariatric surgery

Answer 35

Definition of surgical success: \> 50% reduction in excess weight (the difference between actual and ideal). * Reduces diabetes risk (by 72%) * Reduces serum triglycerides (by 50 – 60%) * Increases HDL levels (by 13 – 47%) – NOTE: low triglycerides often cause an increase in HDLs * Reduces fatty liver * Reduces HYPERTENSION * Post-operative mortality is relatively small = 0.1 – 2%

Question 36

Bariatric surgery and Hba1c

Answer 36

HbA1c (measured in obese diabetics) is reduced more with gastric banding than with medical therapy. The biggest reduction of HbA1c is seen with biliopancreatic diversion surgery.