MG: CT L2

Cholesterol in the membrane:

Decreases permeability and increases fluidity

Why are lipids transported in lipoproteins

Because lipids are not water soluble

4 Types of lipids

• Fats (triglycerides)

• Steroids (lipids that do not contain fatty acids like cholesterolm testosterone)

• Phospholipids (glycerol + phosphate + two fatty acids)

• Waxes ( alcohol with fatty acid is water proof)

Saturated vs unsaturated

Saturated: No double bond, causes less fluidity

Unsaturated: Cis or Trans, double bond, causes more fluidity. Cis causes more fluidity than Trans.

Trans and saturated fats are the ”bad fats”

Too much saturation in membrane:

-Decreased fluidity

-Reduced permeability

-Impaired protein perfusion

Which lipoprotein has the highest cholesterol content

LDL

APO proteins

ApoB-48: Exogenous pathway for chylomicrons

ApoB-100: Endogenous pathway for VLDL, IDL, LDL

ApoA1 or apoA2: Reverse transport HDL

cholesterol sources

80% produced by liver. The rest from food. HMG-CoA important enzym in liver for cholesterol synthesis. 

Exogenous lipid pathway

Fats and cholesterol in the gut are broken down by bile. TG and Cholesterol are taken up by chylomicron. Lipoprotein lipase breaks the TG into FFA and glycerol and secretes them into the peripheral tissue. The remnant Cholesterol esters go to the liver. 

Endogenous lipid pathway

Cholesterol and TG are taken up by VLDL. Lipoprotein lipase hydrolyses TG into FFA and glycerol and secretes them into peripheral tissue. VLDL becomes LDL and returns to the liver to release left over CE. 

Reverse cholesterol transport

C can be taken up from peripheral tissue with HDL. CEPT (Cholesteryl ester transfor protein) can transform HDL into LDL and LDL can go back to the liver to release its contents.

LDL receptor activation

LDL receptor is activated and LDL with receptor is internalized. Receptor is reused or broken down. CE from LDL is made into Cholesterol in a lysosome. Cholesterol inhibits this enzym HMG CoA reductase as a sort of negative feedback.

Familial hypercholesterolaemia (FH)

Increased cholesterol levels in blood due to mutation. 

-LDL Receptor does not work: Liver keeps producing more cholesterol in absence of the negative feedback cholesterol has on itself when released from LDL inside. 

-PCSK9 enhanced concentration.PCSK9 causes degradation of LDL receptors. When the PCSK9 concentration is enhanced there are way less LDL receptors.

-LDL cannot recognize LDL receptor due to mutation in APOB gene. 

Hyperlipoproteinaemia treatment

Based on risk for cardiovascular disease. First adapt lifestyle, after pharmocology

Feedback from cholesterol in liver cell

-Inhibits HMG CoA reductase so no new cholesterol synthesis

-Downregulates LDL receptor

Atherosclerosis

Endothelial dysfunction → Adhesion → monocyte migration → LDL leak → Oxidative LDL due to free radicles → endo/SMC containing a lot of oxLDL (foam cells) → Fatty streaks → Proliferation → Plaque 

Statins

Inhibits HMG CoA reductase. Cholesterol is no longer made but is needed for bile so now it has to be taken up decreasing cholesterol blood concentrations.

Do not use with compounds that inhibit Cyp450, because statins are broken down by it

Side effects and contraindications of statins

Wel tolerated however:

Muscle ache and breakdown, kidney failyre with cyp450 inhibitors or fibrates. allergic skin reactions, small liver damage. Some statins displace coumarins from plasma proteins, can lead to bleeding disorders.

Contraindications: Liver disease, pregancy.

Resins mode of action

Block reuptake of bile (with cholesterol) by the liver resulting in cholesterol staying in the GI tract. Also results in an increase of LDL receptors (because cholesterol is still needed to make new bile)

Often add on therapy

They bind a lot of other compounds in the GI tract as well and can also be used with digitoxin intoxication. 

Resins compounds

Cholestyramine, colestipol

Side effects resins

Steatirrhoea (oily diarhoea), Constipation, lack of fat soluble vitamines, Poor sense of taste (Colestyramine), reduced absorption of compounds. 

Fibrates mode of action

Activate the PPARalpha receptor in the nucleus of liver cells. PPAR-RXR complex binds to PPREs on target genes. 

-LDL particle size up (more uptake liver)
-HDL synthesis up 

-Reverse cholesterol transport up
-Lipoprotein lipase is enhanced therefore less inflammation and triglycerides. 

Resulting in more breakdown and uptake of cholesterol

Fibrates side effect

Stomach feeling full (dyspesia), Diarhhoea. High plasma concentrations cause displace of other drugs bound to plasma protein increasing side effects of these. 

Ezetimibe

Inhibits NPC1L1. NPC1L1 is present in liver and endothelial cells in Gi tract facilitating cholesterol absorption. No effect on vat soluble vitamines triglycerides or bile acids.

Can be used as an addition to statins.

Alirocumab and Eolucumab

PCSK9 inhibitors. PCSK9 normally binds to LDL receptors to induce breakdown, they stop this. Resulting in more cholesterol uptake by the liver.

Omega 3 fatty acids

EPA/DHA. DOES NOT LOWER LDL BUT INCREASES IT. But is usefull with hypertriglyceridemia. Because it will lower TG.