Module 5 Part I

Identify the structural features of triglycerides.

• Glycerol backbone

• carboxylate ester

• hydrocarbon side chain

• different fatty acids

• FAs can have different side chain lengths.

• FAs can have saturated side chains.

• FAs can have unsaturated side chains.

• fuel

• aid absorption of fat-soluble vitamins

Identify the structural features of phospholipids

• glycerol backbone.

• carboxylate ester

• hydrocarbon side chain

• phospho-ester

• different fatty acids

• FAs can have different side chain lengths.

• FAs can have saturated side chains.

• FAs can have unsaturated side chains.

• Fuel

• membrane

Cholesterol structure

• synthesized in vivo.

• animal source.

• bile precursor

• steroid precursor

• membrane structure

lipoprotein complexes

• lipoprotein particles are complexes containing proteins and lipids

• protein component consists of apoprotein – many members of this family

• lipoprotein:

  • core of cholesterol esters and triglycerides

  • phospholipids, free cholesterol and apoproteins form outer layers.

What are the classes of lipoprotein complexes?

Classified according to density:

• chylomicrons

• very low-density lipoproteins

• remnant particles, including intermediate-density lipoproteins

• low-density lipoproteins

• high-density lipoproteins

Used to transport of lipids to cells – cell-free lipids are poorly water saoluble

How are lipids absorbed from the gut?

How are chylomicrons made?

Explain the formation of chylomicrons synthesis and secretion

• dietary triglycerides are digested to monoglycerides and fatty acids in the intestinal lumen.

• monoglycerides, free fatty acids and cholesterol are absorbed at enterocyte brush border and cross apical membrane of the enterocyte.

• lipid droplets formed in the ER membrane are packaged into pre-CMs and transported to the Golgi for processing.

• mature CM particles exit basolateral membrane by exocytosis as secretory vesicles.

• secreted CM particles move through lamina propria, enter lacteals, and are activity transported in lymphatic vessels of increasing size before being released into circulation

Chylomicrons - structure and composition

• protein and lipid complex

• 50-200 nm in diameter

• high proportion of triacylglycerol (85%)

• transport dietary triglycerides from intestine to tissues

VLDL - structure and composition

• protein and lipid complex

• 28-70 nm in diameter

• approx. 50% triacylglycerols

• transport TAGs synthesised in liver to adipose tissue and muscle

LDL - structure and composition

• protein and lipid complex

• 20-25 nm in diameter

• high in cholesterol (8%, 37% cholesterol esters).

• protein 23%

• formed from VLDL that has lost most of TAGs

• carry cholesterol to non-hepatic tissues with apoB-100 receptors

HDL - structure and composition

• 8-11 nm in diameter protein and lipid complex

• cholesterol 2%, cholesterol esters 15%, protein 55%

• formed in liver as small protein-rich particles

• contain enzymes to convert cholesterol from remnant chylomicrons and VLDL cholesterol to esters

• collect cholesterol from peripheral tissues and return to liver

What are the three main functions of apolipoproteins

1. help solubilize cholesterol esters and triglycerides

2. regulate reactions of lipids with enzymes:lecithin: cholesterol acyltransferase, lipoprotein lipase, hepatic lipase

3. bind to cell surface receptors, determining the sites of uptake and rates of degradation of other lipoprotein constituents.

Apoprotein B

• ApoB is the main class of non-exchangeable apoproteins triglyceride-rich lipoproteins.

• ApoB-48 is produced in the intestine and is a component of chylomicrons.

• ApoB-100 is produced in the liver and is a component of LDL, IDL, VLDL

• ApoB-100 is the ligand for LDL receptor that permits LDL uptake.

• ApoB-100 is encoded by the APOB100 gene

• APOB100 gene mutations are associated with premature atherosclerosis

Apoprotein C-II

• ApoC-II is an exchangeable apoprotein found on triglyceride-rich chylomicrons, VLDL, IDL, HDL

• ApoC-II is a cofactor of lipoprotein lipase (LPL) that hydrolyses lipoprotein TG

• ApoC-II is encoded by the APOC2 gene

• APOC2 mutations are associated with hypertriglyceridemia

What is the fate of chylomicrons

1. Go to lacteals – lymphatic capillary in villi

2. Reach the bloodstream near the heart.

3. Deliver most of TG to adipose tissue and/or muscle

4. Degraded by different lipoprotein lipase in different tissues

5. Lipoprotein lipase is activated by apolipoprotein C-II made in liver and incorporated into chylomicrons

6. Lipoprotein remnants – cholesterol, apolipoproteins, phospholipids taken up by liver using apolipoprotein E

7. All dietary cholesterol is eventually transported to the liver

Functional role of lipoprotein lipases

• Hydrolyse TG into two free fatty acids and one monoacylglycerol

• Attached to luminal surface of endothelial cells in capillaries of adipose tissue

• Ligand/bridging factor for receptor-mediated lipoprotein uptake

• Hydrolyses extracellular triglycerides in lipoprotein complexes

Insulin activates lipoprotein lipase

Sites of cholesterol absorption and recovery

• Plasma cholesterol is taken up by the liver, which converts cholesterol to bile salts by cholesterol-7-a-hydroxylase or packages it into LDL

• Bile salts transported to gall bladder

• Bile secreted into duodenum to aid lipid absorption, including cholesterol

• Bile salts reabsorbed from the ileum.

• Bile salts transported to liver and negatively regulates cholesterol-7-a-hydroxylase activity

In the liver

Before a meal:

• Increase in cholesterol – exogenous and endogenous

• Increase in fatty acids – exogenous from chylomicron remnants

• Increase in fatty acids - endogenous formation from glucose

Between meals or if stressed:

• Increase in fatty acids from adipose tissue

After a meal:

• Increase in TG synthesis from fatty acids and glycerol

• Increase in VLDL production

• VLDLs are used to transport TG to peripheral tissues for storage or energy use

• VLDL remnants form LDLs

Endogenous triglyceride synthesis and delivery

• After a meal: LPL near adipose tissue is activated by insulin to store triglycerides (TG)

• Between meals: skeletal muscle LPL is active and provides TG as a source of energy

• When lipoprotein levels are lowest, heart muscle LPL has highest avidity for TGs and therefore heart continues to get energy

Explain the process of cholesterol metabolism

First process

1. Incorporated into VLDLs

2. delivered to cells in LDLs

3. esterification by lecithin: cholesterol acyl transferase

4. retrieved from cells in HDL’s

LDL metabolism

• 70% of cholesterol is in LDLs

• LDLs are transported to liver or peripheral tissue

• LDLs are taken up into cells intact

• Degradation of constituents occurs

• If no receptors LDLs can be taken up by scavenger cells (macrophages) leading to atherosclerosis

Delivery of Cholesterol to Peripheral Tissues

Uptake of Lipids from LDL

Complexes

• LDL binds to ApoB-100 

• receptor-mediated endocytosis

• LDL particles are degraded by lysosomes

What is the fate of HDL complexes

• HDLs collect cholesterol

• LCAT is essential for the collection by HDL

• CETP assists in removal of cholesterol from peripheral sites

• HDLs are taken up into liver

• HDLs exchange cholesterol and apolipoproteins with other lipoproteins

Cholesterol esterification by Acyl-CoA:cholesterol acyltransferase (ACAT)

a) ACAT in the endoplasmic reticulum (ER) catalyses the covalent esterification of cholesterol by long-chain fatty acyl-CoAs to form cholesterol esters

b) Free cholesterol is found mainly in the plasma membrane & lysosomal membrane; transported by NPC1 and NPC2

lysosomal proteins to ER. Elevated cholesterol levels in ER inhibit cholesterol biosynthesis & decrease low-density

lipoprotein (LDL) receptors, increase cholesterol ester synthesis by ACAT enzymes. Cholesterol ester products of

NPC1/NPC2 the ACAT reaction are either stored in cytosolic droplets or secreted from cells as components of apoB-containing lipoproteins. In hepatocytes, cholesterol can also be converted to bile acids.

Recovery Pathway of Cholesterol from Peripheral Tissues

Exogenous pathway of lipid metabolism

Endogenous pathway of lipid metabolism

Reverse cholesterol transport

Lecithin:cholesterol acyltransferase (LCAT)

• LCAT is a key enzyme in lipoprotein metabolism that enables the maturation of high-density lipoprotein (HDL) particles.

• LCAT is activated by Apo A-1 and catalyses esterification of free cholesterol on the surface of HDL to form cholesteryl esters.

• Cholesteryl esters partition into the lipoprotein core, resulting in the formation of mature spherical HDL particles.

LCAT and HDL maturation – Cholesterol esterification

Role of cholesteryl ester transfer protein

• Cholesteryl ester transfer protein (CETP) promotes the transfer of cholesteryl esters from HDL to apoB-containing lipoproteins: VLDL, VLDL remnants, IDL, and LDL.

• Deficiency of CETP is associated with increased HDL levels and decreased LDL levels, which is antiatherogenic