Lipoproteins

Five Types of Lipoproteins

chylomicrons, VLDL, IDL, LDL, HDL – different density, composition, site of formation, function

they carry lipids and cholesterol to and from cells
all have nonpolar core (triglycerides, cholesterol esters), polar surface (phospholipids, cholesterol, apolipoproteins)

apolipoproteins all act as receptor ligands or activators

(1) chylomicrons - made in intestine – carry triglycerides to adipose tissue and dietary/intestinal cholesterol to liver

chylomicrons Þ adipose tissue (take triglyceride) Þ chylomicron remnants Þ liver

characteristics: least dense (<0.95), very large ("micron") – almost visible, very short lived (t_½ = 4-5 minutes)

contains mostly triglyceride (85-90%), some cholesterol (2-4%, all from diet), very little protein (1-2%)

apolipoprotein content: initially apoB-48 (only seen here) and apoA

HDL lipoproteins donate apoE and apoC in the serum (increasing protein concentration 2-3x)
HDL also donates cholesterol and takes phospholipid

Chylomicron Remnant – result of removal of triglycerides – smaller, lower TG content but more cholesterol ester

taken up by liver through apoE receptors – triglycerides, choletsterol esters, apolipoproteins broken down

(2) VLDL – made in liver; carry triglycerides to adipose tissue, skeletal muscle, and heart – some also made in intestine

characteristics: low density, much smaller than chylomicrons, intermediate lifespan (t_½ = 1-3 hours)

contains about half triglyceride (45-65%), produced de novo (from CHO/amino acids) or from blood
also some cholesterol (16-22%)

apolipoproteins: initially apoB-100 and apoE – serum HDL adds apoC and cholesterol, takes phospholipid

(3) IDL – derived from VLDL by partial triglyceride hydrolysis by lipoprotein lipase; deliver endogenous cholesterol to liver

thus, IDLs are the functional equivalent of chylomicron remnants

characteristics: between VLDL and LDL (below) in size, density, and composition; very short lived

apolipoproteins: they are derived from VLDL, so they have the same apolipoproteins (apoB-100, apoE)

apoC is inactivated due to lipoprotein lipase (see "lipoprotein lipase" below)

(4) LDL – metabolized from IDL in blood and liver; carries cholesterol to body tissues

characteristics: smaller, higher density, and more protein than VLDL and IDL; not much triglyceride (4-8%)

more cholesterol than any other lipoprotein (45-50%, more than 1500 cholesterol ester molecules)
long lifespan (t_½ = about 1 day) – comprises about ½ of total plasma cholesterol

apolipoproteins: contains ONLY apoB-100 (carryover from IDL) – the other apolipoproteins go to HDL

Positive cholesterol balance will result in excess LDL Þ excess cholesterol deposition; carries "bad" cholesterol

3 ways to remove LDL

(1) B-100:E receptor (high affinity)

(2) low affinity receptor (concentration dependent – activity Ý when Ý LDL)

(3) scavenger cell pathway – tendon or splenic macrophages, hepatic kupffer cells, bone marrow histiocytes, etc.

the scavenger pathway accounts for 15% of total LDL removal, but 100% in hypercholesterolemia

lipoprotein(a) – LDL with apoliprotein(a) linked covalently to B-100 – causes increased risk of coronary artery disease

apolipoprotein(a) looks like plasminogen, but does not have its protease activity

three mechanisms of damage due to apolipoprotein(a):

(1) competes with plasminogen for binding sites on clots/plasminogen activator enzymes – slowed clot breakdown
(2) binding to remnants of old clots in arterial wall or to ECM signalling endothelial cells to grow inappropriately
(3) macrophages take it up and become foam calls that release growth factors that facilitate atherosclerosis

(5) HDL – removes cholesterol from extrahepatic cells and transfers it to lipoproteins returning to liver (remnants, IDL, LDL)

characteristics: smallest, highest density, highest protein content and lowest triglyceride among lipoproteins

very long life (t_½ = 4-6 days)

apolipoproteins: HDL originating in liver has high apoC and apoE and low apoA; opposite is true of intestinal HDL

since HDL rapidly exchanges with other lipoproteins, there is soon a uniform quantity of all apolipoproteins

apoA-I activates LCAT (lecithin cholesterol acetyl transferase) that esterifies the cholesterol to lecithin

LCAT is related to ACAT (acyl cholesterol acetyl transferase) in tissues

apoD causes transfer of esterified cholesterol to another lipoprotein

since HDL removes cholesterol, it is antiatherogenic and thus carries "good" cholesterol

Lipoprotein Lipase

cleaves triglycerides into fatty acids and 2-monoglyceride (probably made into glycerol)

converts chylomicrons Þ remnants or VLDL Þ IDL

most common in capillaries of adipose, heart, red skeletal muscle, lactating mammary gland

made in cells, expressed on luminal endothelium; released from surface by heparin

2 isoforms – rate of synthesis/degradation controlled by insulin levels (low during fasting):

(1) heart – low K_m, functions during post-absorbative state (ß activity when Ý insulin, so active during fasting)

(2) adipose – high K_m, more active after fatty meal/when VLDL secreted rapidly (Ý activity when Ý insulin)

apoC-II specifically activates lipoprotein lipase (it also inhibits binding to liver apoE receptors (E and B-100:E)

lipoprotein lipase inactivates apoC-II, allowing uptake by liver through the apoE receptors

Cholesterol Homeostasis

Cholesterol Synthesis – in endoplasmic reticulum of virtually every cell

from acetyl CoA (all 27 carbons from acetyl CoA)

acetyl coA + acetoacetyl CoA Þ HMG CoA (b-OH b-methyl glutaryl CoA) – this is 5 carbons long (OH and CH3 both on beta carbon)

converted to mevalonic acid (6C) by HMG CoA reductase – rate limiting enzyme in cholesterol synthesis – cholesterol feedback

lose carboxyl group, add phosphates to produce isopentyl pyrophosphate Þ geramyl-PP Þ farnasyl-PP (15 carbons) – used to do other things

e.g., farnasyl group anchors proteins to cell membrane or make heme/ubiquinone
thus, long term inhibition of HMG CoA reductase can cause liver damage

farnasyl Þ squalene (20 carbons) Þ cyclized to lanosterol (30 carbons)

lanosterol is used to make cholesterol (27 carbons)

Cholesterol has one OH group, at C-3, that is used to esterify fatty acids

Control of Synthesis – cAMP/glucagon ß , insulin Ý

Cholesterol Degradation – cholesterol can be modified to make hormones

but, since it cannot be oxidized, eventually ALL cholesterol must exit via feces

The Role of Lipoproteins

two pathways – cholesterol ester deposit if not balanced (see figure for details):

(1) Exogenous Pathway

Cholesterol packaged in chylomicrons Þ circulation

Lipoprotein lipase converts to remnant

Liver takes up remnant via apoE receptors

(2) Endogenous pathway

VLDL made in the liver Þ circulation

VLDL Þ IDL by lipoprotein lipase; HDL adds cholesterol

Some IDL goes to liver via high affinity B-100:E receptor

Most IDL converted to LDL, which binds extrahepatic B-100:E

In the liver, cholesterol has two possible fates:

(1) repackaged into VLDL (Þ endogenous pathway),

(2) converted to bile acids by adding 2^nd OH at C-7, then addition of taurine or glycine to form cholic acid derivative

rate of hydroxylase is believed to control cholesterol level
bile acids assist in digestion of lipids, but 10% are lost in feces – this is the only way cholesterol is eliminated

How can serum LDL cholesterol be reduced?

(1) less entry – lower dietary cholesterol, but hard to do and not very effective by itself

(2) less synthesis – lower intake of fats (substrate for HMG CoA reductase)

also could use HMG CoA reductase inhibitors (analogs of mevalonic acid), but expensive

(3) more elimination – cause more bile acids to be secreted

bile acid sequesterer (such as resin), but produces reduced vitamin absorption and constipation

Familial Hyper- and Hypolipidemias

Hyperlipidemias

(1) Familial Hypercholesterolemia (type 2 hyperlipidemia) – defect in ability to produce LDL (B-100:E) receptors

receptor exists on chlatherine coated pits – endocytosis, fusion with lysosomes

could be problem in promoter, DNA sequence, addition of O-glycans in Golgi, or transport of receptor

e.g., single mutation in cytoplasmic domain Þ many heart attacks at early age

increased LDL cholesterol – to 300 mg/dl in heterozygotes, 600-1000 in homozygotes (normal = 100 mg/dl)

LDL metabolized only by scavenger pathway, so not possible to lower below 500, even with all current therapies

gene therapy to correct? – adding gene can lower diseased rabbits 900 Þ 500, to 200 with drugs

(2) Familial Dysbetalipoprotinemia (type 3 hyperlipidemia) – production of abnormal apoE

abnormal apoE shows reduced interaction with both E and B-100:E receptors

results in accumulation of chylomicron remnants and IDL in plasma as well as an abnormal lipoprotein, b -VLDL

also rise in serum cholesterol/triglycerides

xanthomas are common; responds to decreased dietary cholesterol, clofibrate, nicotinic acid

Hypolipidemias

(1) Abetalipoproteinemia – no chylomicrons, VLDL, or LDL in plasma, so all major plasma lipids reduced

almost no plasma triglycerides, 25% of normal phospholipids, cholesterol less than 50 mg/dl
maybe defect in synthesis of apoB (remember, apoB-48 in chylomicrons, apoB-100 in others)
triglycerides accumulate in liver and intestinal mucosa
RBCs have abnormal shape (acanthocytes) because of disruption in membrane lecithin:sphingomyelin ratio

(2) Hypobetalipoproteinemia – same changes in plasma lipoproteins and lipids as with abetalipoproteinemia

with this disease, even heterozygotes cannot maintain normal LDL

(3) Familial HDL Deficiency (Tangier disease) – no HDL in plasma – produce normal chylomicrons, IDL, VLDL

normal apoA-I, apoA-II and LCAT (normally on HDL); also normal lipoprotein lipase
triglycerides increased, LDL cholesterol is low, but pathological accumulation of cholesterol esters in tissues
unknown defect – maybe decreased production of apoA or assembly of HDL