BCH210 - Lecture 21 - Lipoproteins

lipoproteins

-are the transport molecules for hydrophobic TAGs and cholesterol esters throughout the body

-they have a thin monolayer of phospholipids and cholesterol (very hydrophobic, so it has a hydrophobic core), (can’t carry much cholesterol (monolayer))

-the polar portions of the molecules face the aqueous exterior, while the hydrophobic ones face the hydrophobic interior

-are made in the liver and intestine

apoproteins

-are on the surface of the lipoprotein and are oriented with hydrophilic side chains exposed and hydrophobic side chains buried inside the molecule

-help with targeting and binding to cells and other proteins via non-covalent interactions for lipoprotein metabolism in circulation

cholesterol

-is crucial for membranes and is metabolized to produce hormones, bile salts and vitamin D3

-is made from Acetyl CoA in the cytoplasm of liver cells using carbons from fat/protein/carbohydrate catabolism

-is found in the diet (mainly animal-based products) but it is also synthesized in the liver (~800 mg/day)

-can be modified to a hydrophobic, acyl-carrying molecule called a cholesterol ester (CE) by acyltransferases

-the production of cholesterol requires NADPH and ATP (because anabolic pathway) and is regulated by inhibiting an enzyme called HMG-CoA reductase (important for regulation) via phosphorylation or statins

what are the 4 competitive inhibitors of cholesterol synthesis?

1. compactin

2. lovastatin

3. simvastatin

4. pravastatin

**statins*

what is regulation dependent on?

-its dependent on how molecules bind to our enzymes

competitive inhibition

-increase Km

-Vmax still achieved

how do lipid transport via lipoproteins?

-As they travel through the body, fatty acids and cholesterol are transferred to the tissues to build membranes, produce energy or other molecules

-Whatever doesn’t get used returns to the liver as lipoprotein remnants for recycling. Additional cholesterol and/or TAGs (comes from acetyl CoA) are synthesized for the production of new lipoproteins to be sent out

what leads to high cholesterol and cardiovascular disease (CVD)?

-excess synthesis of fats, defects in the receptors that recycle lipoproteins, or problems with the expression and/or activity of HMG-CoA Reductase can disrupt the balance of lipid metabolism and lead to these issues

cardiovascular disease (CVD)

-too many lipoproteins floating around in the bloodstream and not being used

-High LDL and low HDL levels are risk factors for this disease

cholesterol metabolism

-it requires ATP and NADPH

-is an anabolic pathway

how is cholesterol metabolism regulated?

-using phosphorylation or statins to inhibit HMG-CoA reductase (an enzyme)

what are the 4 types of lipoproteins?

1. chylomicrons

2. very low density lipoproteins (VLDL)

3. high density lipoproteins (HDL)

how are different lipoproteins differentiated?

-the different lipoproteins can be differentiated by their individual components (apoproteins, % TAGs, % cholesterol, % protein)

chylomicrons

-are made in the small intestine from the diet, are the largest and contain the most TAGs, as well as an apoprotein known as Apoprotein 48

very low density lipoprotein (VLDL)

-is sent out by the liver to distribute TAGs and cholesterol and contains the ApoB100 protein (when synthesizing cholesterol)

-it binds to lipoprotein lipase, which hydrolyzes and releases TAGs (uyou lose fatty acids) producing Intermediate Density Lipoprotein (IDL), and then eventually Low Density Lipoprotein (LDL) → structure gets smaller and this is bad for cholesterol and its not from the original cholesterol its from the lipoprotein

high density lipoprotein (HDL)

-is the ‘good cholesterol’ that contains the LCAT enzyme that picks up cholesterol (& CEs → cholesterol ester) for transport back to the liver for breakdown and recycling

-does reverse cholesterol transport

membrane-bound enzymes

-help release free fatty acids for cellular use for lipoprotein metabolism in circulation

what area of the body makes the most cholesterol?

-the liver makes majority of the cholesterol in your body

**your diet makes some but not as much

what is the liver responsible for?

-is responsible for monitoring cholesterol levels and for lipoprotein recycling and the synthesis of new cholesterol

-increased cholesterol intake, synthesis in the liver or decreased lipid turnover and/or cellular use can lead to cardiovascular disease

what have oxidized LDL particles been found to be the principal components of what?

-oxidized LDL particles have been found to be the principal components in arterial plaques resulting in heart attack or stroke that can lead to blockage

how can you improve cardiovascular health?

-exercise and proper diet can help increase HDL and lower LDL levels

-proper diet includes monitoring fat intake (decreased trans and saturated fats) but also caloric intake

-stop smoking and decrease stress to lower your blood pressure and prevent arterial damage where oxidized LDL accumulates

-last resort – statin drugs

do men or women have higher HDL levels?

-women have higher HDL levels

what plays a major role in the regulation of cholesterol levels?

-the enzymes and receptors in your liver play a major role in the regulation of cholesterol levels (making HDL and VLDL)

what is the regulated step in cholesterol production?

-HMG-CoA reductase is the regulated step in cholesterol production