H 3 C C C C C C C C C C C C C C C2468

COO-10121416

H 3 C C C C C C C C C C C C C C C2468

COO-10121416

H 3 C C C C C C C C C C C C C C C2468

COO-10121416

H 3 C C C C C C C C C C C C C C C2468

COO-10121416

H 3 C C C C C C C C C C C C C C681012141618

C4

C COO-C2

H 3 C C C C C C C C C C C C C C681012141618

C4

C COO-C2

H 3 C C C C C C C C C C C C C C681012141618

C4

C COO-C2

Palmitic acid

H 3 C C C C C C C C C C C C C C C2468

COO-10121416

HO

Cholesterol

Cholic acid

HO OH

OHO-

O

Na+

CH2

COO-HN

glycocholic acid

sodium cholate

Cholesterol• exogenous (dietary) cholesterol delivered to liver via chylomicron remnants.• endogenous cholesterol synthesized primarily in the liver from AcCoA (extrahepatic tissues also synthesize cholesterol)• in the liver, cholesterol is either converted to bile salts or to cholesterol esters and packaged into VLDLs. • Peripheral tissues obtain most of their exogenous cholesterol from LDLs and convert it back to cholesterol for use in membranes or store in cholesterol ester droplets.• LDLs deliver cholesterol to the tissues – HDLs circulate it back to the liver.• Excess cholesterol is disposed of by the liver as bile salts.

•Average serum cholesterol ~175mg/100ml

Lipid transport

• triacylglycerides, cholesterol, phospholipids

• dietary lipid transport –chylomicron

• endogenous lipid transport (VLDL, IDL, LDL, HDL)

pancreaticlipases

intestinal lumentriacylglycerols

FFA + monoacylglycedrols

bile acidscholesterol

micellesmicellesepithelial cellstriacylglycerols

absorbed by intestinal epithelial cells and reconverted to triacylglycerols

•Packaged into chylomicron•Released into lymphatic system and then via capillaries to blood stream

chylomicron

•acted upon by lipases on cell walls of capillaries in tissues

FFA • taken up by tissues

energy production

reconversion to TAGs in adipocytes for storage

hormone sensitive lipasesFFAreleased to circulatory system and combine with albumin fordelivery to tissues

Dietary uptake and distribution of fatty acids

Why do we need lipoproteins?

• Triacylglycerides (TAGs) + cholesterol (Chol) are nonpolar molecules → insoluble in H2O

• TAG + Chol must be packaged within a polar shell in order to be transported through the blood to the various tissues

• This is accomplished by combining nonpolar lipids w/ amphipathic lipids →(a polar water-soluble terminal group attached to an H2O -insoluble hydrocarbon chain)

Lipoproteins & Apolipoproteins

Lipoproteins (LP) function: transport of cholesterol + esterified lipids in

blood structure:

1) polar shell ---single phospholipid (PL) layer: head groups directed outward

-Chol-apolipoproteins

2) nonpolar lipid core -hydrophobic TAG(triacylglycerol)-cholesteryl ester (CE)

Apolipoproteins

• Provide structural stability to Lp

• Serve as ligands for interaction w/Lp receptors that help determine disposition of individual particles

• Act as cofactors for enzymes involved in plasma lipid and Lp metabolism

There are many types of apolipoproteinsa

Apoprotein Lipoproteins Function(s)

Apo B-100 VLDL, IDL, LDL 1) Secretion of VLDL from liver 2) Structural protein of VLDL, IDL, and HDL 3) Ligand for LDL receptor (LDLR)

Apo B-48 Chylomicrons, remnants

Secretion of chylomicrons from intestine; lacks LDLR binding domain of Apo B-100

Apo E Chylomicrons, VLDL, IDL, HDL

Ligand for binding of IDL & remnants to LDLR and LRP

Apo A-I HDL, chylomicrons 1) Major structural protein of HDL2) Activator of LCAT

Apo A-II HDL, chylomicrons Unknown

Apo C-I Chylomicrons, VLDL, IDL, HDL

Modulator of hepatic uptake of VLDL and IDL (also involved in activation of LCAT)

Apo C-II Chylomicrons, VLDL, IDL, HDL

Activator of LPL

Apo C-III Chylomicrons, VLDL, IDL, HDL

Inhibitor of LPL activity

Lipoprotein Structure

Lipoproteins• hydrophobic core (TAGS, cholesterol esters)• hydrophilic surface (P-lipids, cholesterol, and

apolipoproteins)

• Functiontransport of lipids in blood

• Types of lipoproteins(classified according to density)

• very low density (VLDL)• intermediate density (IDL)• low density (LDL)• high density (HDL)Protein content increase, lipid decreases as density increases.

% TAGS

% Protein

Chylomicron VLDL IDL LDL HDL85%

2%

8%

33%

nm

Lipoproteins• Chylomicron:

• 85% TAG, 4% chol., 8% protein• 80 -500nm•formed in intestinal epithelial cells• deliver exogenous TAGS to tissue• ApoCII activates lipases in capillary cell

walls releasing FFA to tissue• chylomicron remnants return to liver where

they bind to ApoE receptor and are taken up• 1/2 life in blood - 4-5 minutes

• VLDL:• 50% TAGs, 22% choles., 10% protein• 30 -100 nm • formed in liver• deliver endogenous lipids to other tissues

(mainly muscle and fat cells)• ApoCII activates lipases in capillary cell

walls releasing FFA to tissue• converted to IDLs and LDL as lipids are

released

• IDL: (31% TAGs, 29% choles., 18% protein) • formed from VLDLs as lipids removed• some IDLs return to liver• rest converted to LDLs by further removal

of lipids

Lipoproteins

• LDL: “bad” cholesterol• 10% TAGs, 45% choles., 25% protein• 25 - 30 nm• formed as lipids removed from VLDLs

and IDLs. • all apolipoproteins lost except ApoB100• bind to LDL receptor via ApoB100 and

taken up by endocytosis by hepatic and other tissues (50-75% taken up by liver).

• Primary mode of cholesterol delivery to tissues.• Synthesis of LDL receptor is inhibited by

high levels of intracellular cholesterol and stimulated by low levels of cholesterol.Therefore, cholesterol uptake is closly matched to intracellular cholesterol levels.

• HDL: “good” cholesterol• 8% TAGs, 30% choles., 33% protein• 7.5 - 10 nm• formed in liver• scavenge cholesterol from cell surfaces

and other lipoproteins and deliver it to liver.• Convert cholesterol to cholesterol ester• bind to “scavenger receptor” on liver cell

surface - cholesterol esters taken up and HDLs released and reenter circulation.

Lipoproteins

Intestine Liver

Dietary lipids

chylomicron

Peripheral tissues

Dietary lipids

chylomicron

LDLs

TriacylglycerolsFFA

monoacylglycerols

Cholesterol

Cholesterol esters

Triacylglycerolscholesterol

Cholesterol esters

VLDLs

HDL

HDLs

Intestine Liver

Dietary lipids

chylomicron

Peripheral tissues

Dietary lipids

chylomicron

TriacylglycerolsFFA

monoacylglycerols

Cholesterol

Cholesterol esters

Fig 16.30Distribution of endogenous lipids The Exogenous Pathway

LPLs activated by ApoCII

Chylomicronremnantsacquire

ApoE, CIIand others

ApoE/LDLRmediated

uptake

Liver

Peripheral tissues

LDLs

TriacylglycerolsFFA

monoacylglycerols

Cholesterol Ester

Cholesterol

Triacylglycerolscholesterol

Cholesterol esters

VLDLs

IDLs

Fig 16.30

Distribution of endogenous lipids The Endogenous Pathway

acquireApoE, CIIand others

LPLs activated by ApoCII

LDLR/ApoE

LDLR/ApoB100

Distribution of endogenous lipids The HDL Pathways

Transport of excess cholesterol from peripheral tissues back to liver for excretion in bile

HDLs act as acceptors for excess chol, Apo, PL derived fromCM, VLDL and LDL

HDLs synthesized by both liver and intestine

Liver

Peripheral tissues

LDLs

TriacylglycerolsFFA

monoacylglycerols

Cholesterol Ester

Cholesterol

Triacylglycerolscholesterol

Cholesterol esters

VLDLs

HDL

HDLs

IDLsCEs

TAGs

Fig 16.30

Distribution of endogenous lipids The HDL Pathways

scavenger receptoruptake of cholesterol

VLDLCholes.