artherosclerosis

Question 1

triglycerides

Answer 1

storage fats (aka fats, neutral fats, triacylglycerol)
3 Fa each in an ester linkage with single glycerol
Simple TGs have the same kind of FA in all 3 positions (18 1 triolein)

Natural occuring TGs are mixed 2-3 different FAs

High Triglycerides- independently predict risk of CVdis
if >1g/dL–> increase risk of pancreatitis

Question 2

Cholesterol

Answer 2

Essential component of membranes, precursor for synthesis of bile acids and steroid hormones, reduces fluidity of membranes, enriched in lipid rafts (signal transduction)

Cytotoxicity- excess–> formation of cholesterol crystals, triggering apoptosis, formation of toxic oxysterols, disruption of membrane domains, artherosclerosis (plaque)

Rate limiting step of cholesterol de novo biosynthesis: HMG CoA reductase (B-HMG CoA to mevalonate) INHIBITED by STATINS

Cholesterol will become bile acids, biliary cholesterol, or cholesteryl Esters (CEs), or tissue converts cholesterol to steroid hormones

Bile acids (gallbladder, taurocholic acid) secreted into small intestine after fatty meal to emulsify fat, to increase lipases

Question 3

Cholesteryl esters (CEs) less polar than cholesterol

Answer 3

CEs contain a FA esterified to the oxygen, CEs become more hydrophobic and enters membranes, transported to lipoproteins to other tissues or stored in liver

Question 4

Lipoprotein particles

Answer 4

lipids are carried thru PM on spherical particles, surface is made of proteins (Apolipoprotiens), free cholesterol and a phospholipid monolayer, interior contains cholesterol, TGs, CEs

Types largest to smallest: Chylomicrons, VLDL, LDL, HDL

Apolipoproteins solubilize the lipoprotein particle in the circulation, structural stability, co-factors for Lipolytic enzyme, ligand for surface receptors

Question 5

Apolipoproteins to know

Answer 5

ApoA-1 : on HDL, Actvates LCAT, interacts with ABC transporter
ApoB-48: on chylomicrons, cholesterol transport/clearance
ApoB100: on VLDL and HDL, binds to LDL receptor
ApoC2: on Chylomicron, VLDL, HDL: activates lipoprotein lipase
ApoC3: on Chylomicron, VLDL, HDL: inhibits lipoprotein lipase
ApoE: on chylomicrons, VLDL, HDL, triggers clearance of VLDL and chylomicron remnants

Question 6

Lipid absorption

Answer 6

Western diet: 100 g of fat, long chain TGs 92-96% of the total, (membrane lipids remaining)

20 g of phospholipids (mainly phosphatidylcholine) and 1-2 g of cholesterol enter duodenum in bile

humans absorb >95% of TG and 50% of the cholesteron

Question 7

Dietary FA absorbtion

Answer 7

Bile salts emulsify fat in small intestine, forming mixed micelles, intestinal lipases degrade TGs, FAs and other break downs are taken up by intestinal mucosa (NPC1L1, inhibited by ezetimibe) and converted into TGs
TGs are incorporated with cholesteron and APOs into chylomicrons via ApoC2 (move through lymphatics and BS to tissue)

lipoprotein lipase activated by apoC2 in the capillary converts TG–> FA and glycerol

FA are oxidized as fuel or reesterified for storage

ABCG5/G8 export plat sterols back into intestinal lumen (

Question 8

chylomicrons carry dietary TG

Answer 8

synthesized from the FAs of dietary TGs and cholesterol absorbed from the small intestine

Function: transport dietary TGs from the small intestine to peripheral adipocytes and the liver, essential for absorption of dietary fat and fat soluble vitamins

Composition: very high fat content (98%) 85% is FAs of dietary TGs (10:1 tg to chol)

Apolipoproteins on chylomicrons (ApoB48, C2, E). Apo48 (apolipoproteins synthesized by intestinal epithelial cells -B48) others acquired from HDL (Apo E and C123) after chylomicrons have been secreted into the lymph and enter plasma. ApoB48 synthesized only by intestinal epithelial cells is unique to chylomicrons. ApoC2 activates lipoproteins lipase to allow FFA release for fuel in adipose tissue, heart, sk muscle

Question 9

Lipoprotein Lipase (LPL) hydrolyzes TGs

Answer 9

LPL is bound to capillary endothelium in heart, sk muscle, adipose and mammary glands

LPL-mediated hydrolysis of TG is required for delivery of FAs to adipose and muscle (for oxidation) takes place at vascular endothelial surface

Activated by the presence of apoC2 on chylomicrons and VLDL (TG–>DAG–>MAG), results in shrunken cholesterol rich particle (CM remnant) cholesterol phospholipids and apolipoproteins are transferred to HDL

LPLase defeciency–> high TGs (after 10 hours of fat meal)

Question 10

Chylomicron remnants deposit cholesterol in liver

Answer 10

When chylomicrons are depleted of their dietary TG via LPL remnants go to liver to release their dietary cholesterol (now enriched in cholesryl esters), surface lipids and C proteins are transferred to HDL, ApoB48 is degraded (chylomicron remnants are rapidly removed from circulation via endocytosis at the liver thru ApoE for the LDLR or LDL receptor related protein (LRP)

Question 11

Type 3 hyperlipoproteinemia

Answer 11

Also known as familial dysbetalipoproteinemia

inherited absence of functional ApoE, inhibited remnant clearance LRP or the LDLR, increased TG rich remnant lipoproteins in plasma

Question 12

VLDL

Answer 12

VLDL transports endogenous lipids to peripheral tissues

Produced in liver when TG production stimulated by increased flux of FFAs or by increased de novo synthesis of FAs by liver

Function: transports TG and CEs synthesized in liver to periphery
Comp: lipids (75% TGs) ApoB100, C123, E

Excess carb in diet also made into TG in the liver and packed into VLDL

Question 13

MTP

Answer 13

Microsomal Triglyceride Transfer protein MTP helps transfer TGs to the VLDL core

ApoB100 to form VLDL in Liver, ApoB48 to form chylomicrons (bad MTP–> no chylomicrons,VLDL, LDL)

abetalipoproteinemia

Question 14

Acyl CoA ACAT (transferase)

Answer 14

esterifies free cholesterol to form cholesteryl esters (CEs)

diet or endogenous cholesterol in excess of need for membrane synthesis is metabolized to CE by ACAT for storage

ACAT catalyzes the esterification of cellular sterols with FAs, bile acids

Question 15

VLDL transport TG to adipose tissue and muscle

Answer 15

ApoC2 activates lipoprotein lipase to release FAs

adipocytes take up the FFA, reconvert them to TG and store them in lipid droplets, muscle uses the TG for energy

VLDL remnants become IDL and LDL

VLDL fates are: 40-60% cleared from plasma by the liver via LDL R and LRP which recognize ligands (apoB100 and apoE) on the remnants. LPL and hepatic lipase convert the remainder of the remnants (IDL to LDL) all LDLs are derived from VLDL

The C apolipoproteins and apoE, and surface lipids, redistribute to HDL, the have lost 70% of TG and are enriched in CE

Question 16

LDL deposit cholesterol in peeripheral tissue

Answer 16

VLDL remnants that escape uptake are transformed into LDL

Function (Transport of CE to peripheral cells and HDL derived CE back to the liver

Comp: 70% cholesterol, ApoB100
Plasma clearance of LDL particles mediated by LDL R (ApoB100)

Hepatic LDL receptors remove 75% of all LDL from the plasma (modulate LDL)

Oxidized LDL taken up by M@ scavenger receptors

Question 17

PCSK9

Answer 17

decreases steady state expression of the LDL receptor on hepatocyte

Promotes intracellular degradation of the LDLR

LDLR/PCSK9 complex gets internalized and targeted to the lysosomal compartment for degradation

Prevents LDLR recycling to cell surface, reduces LDLR population on Cell surface, reduces clearance of LDL from circulation

loss of fucntion mutation PCSK9– higher levels of LDLR, Lower LDL and protection from CAD
Gain of funciton mutation– higher LDL (AD hypercholesterolemia)

Question 18

Lp(a)

Answer 18

LDL like particle where apoB100 is covalently bound to apo A

ApoA is expressed liver cells, half life= 3-4 days, risk factor for CVD

Question 19

HDL is atheroprotective

Answer 19

antioxidant, antithrombotic, reduces vascular adhesion on endothelium, stimulates endothelial repair, promotes endothelial function, lowers inflammation, stabilizes plaques

HDL picks up cholesterol from peripheral cells and returns to liver for excretion via bile (lots of protein apoA1 and ApoA2 and C apos (HDL transferred to nascent VLDL and chylomicrons)

Question 20

ABCA1

Answer 20

release free cholesterol to apoA1 to make discoid HDL

efflux of cell phospholipid and cholesterol to apoA1

LCATforms the CE core of HDL