BICH Ex3 Lec 14 - Lipid Processing

Emulsification

The process in the small intestine where amphipathic bile salts are used to break down large lipid droplets into micelles. Allows for solubilization of digested lipids; the polar head groups of the bile salt interact with the aqueous environment while the nonpolar part interacts with the lipids. Necessary for enzyme function as enzymes only function in aqueous environments.

Bile salt

Amphipathic molecule formed in the liver using cholesterol. Surrounds lipids in the small intestine to form soluble micelles.

Pancreatic Lipase

Released by the pancreas. Bound in a 1:1 ratio with colipase, which senses the lipid-water interface of micelles by binding to the polar head groups of bile salts to stabilize the active conformation, allowing micelles to enter the active site for TAG breakdown via ester hydrolysis. No micelles = gate closed, inactive. Micelles present = gate open, active.

Phospholipase

Binds to the polar, external layer of micelles and pulls it apart to create a channel for TAGs to enter the active site and undergo ester hydrolysis. Breaks down TAGs and sends them back into the micelle. Undergoes NO conformational change.

What lipids are produced at the end of digestion by lipases?

DAGs, MAGs, free FAs, glycerols, and some leftover TAGs

Absorption of Dietary Lipids

Broken down lipids are small enough to diffuse into the intestinal mucosal cells with the help of bile salts. Only the lipids diffuse; not the full micelle. Once the TAGs have been absorbed, they can be carried by Fatty Acid Binding Proteins (FABPs) to either the mitochondria (break down for energy) or to TAGs synthesis sites to be turned back into TAGs and packaged into chilomicrons for export.

Fatty Acid Binding Proteins (FABPs)

Present in intestinal mucosal cells, carry broken down lipids to mitochondria (break down for energy) or to TAG synthesis sites for packaging and export. Increases the solubility of FAs in the cell.

Lipoprotein

Complex of proteins and lipids with a non-polar core (full of TAGs and cholesterol esters) and an amphipathic coating (proteins, cholesterol, and phospholipids). Different classifications based on the lipids they carry, where they carry them to, and the ratio of lipids:proteins. 5 types: chylomicrons, VLDLs, IDLs, LDLs, and HDLs.

Chylomicrons

Carry: lipids from digestion

Destination: Intestine → Target Tissues (heart, muscle, adipose tissue, etc)

Highest lipid:protein ratio, largest lipoprotein, only lipoprotein that acts in the exogenous pathway

Synthesized in intestinal mucosal cells, released to intestinal lymphatic vessels for delivery throughout the body

Exogenous Pathway

The pathway for lipids obtained from external sources (diet). The only lipoprotein that acts in this pathway is chylomicrons.

Endogenous Pathway

The pathway for lipids synthesized in the body. Lipoproteins in this pathway include VLDLs, IDLs, LDLs, and HDLs.

VLDLs

Very Low Density Lipoproteins

Carry: TAGs and cholesterol

Destination: Liver → Target Tissues

Chylomicrons get repackaged as VLDLs in the liver

Part of the endogenous pathway

IDLs

Intermediate Density Lipoproteins

Carry: Leftover lipids

Destination: Liver ←→ Target Tissues

Transition particle; VLDLs deliver TAGs then become IDLs to deliver leftover lipids, IDLs accept cholesterol from HDLs to become LDLs. Acts as the switch between TAG to cholesterol transport.

Used in two ways: absorbed by the liver for repackaging, converted to LDLs by picking up cholesterol from HDLs.

Part of the endogenous pathway

LDLs

Low Density Lipoproteins

Carry: Cholesterol; major cholesterol carrier

Destination: Liver → Target Tissues

Made in the liver or by IDL picking up cholesterol from HDL, picks up cholesterol and takes it to where it is needed

Part of the endogenous pathway

HDLs

High Density Lipoproteins

Carry: Excess cholesterol

Destination: Target Tissues → Liver; Reverse Cholesterol Transport

Precursor (nHDL) is synthesized in the liver, picks up excess cholesterol from bloodstream and cells that cannot process it to become HDL. Drops off cholesterol in liver

Part of the endogenous pathway

What is cholesterol needed for?

Cell membrane fluidity, cell signaling, bile synthesis in the liver, and steroid hormone synthesis

What role to HDLs play in the immune system?

They pick up cholesterol from macrophages (a type of white blood cell), without HDLs the immune system would be weakened.

Good vs. Bad Cholesterol

High HDL is GOOD; cholesterol is getting picked up

High LDL is BAD; cholesterol is getting deposited, increased risk for heart disease

Apolipoproteins

The proteins on lipoproteins; each lipoprotein has a unique set of them.

Purposes are to solubilize lipoproteins, act as cofactors for enzymes for lipid breakdown, and bind to receptors of cells to aid in uptake of lipids.

ApoA-I

Apolipoprotein A-1

Homotetramer that wraps around HDL. Binds to ABCA1 and ABCG1 receptors to allow nHDL to uptake lipids, forming mature HDL. Also binds to SRB1 receptor on the liver to allow cholesterol drop-off.

SRB1 Receptor

Receptor on the liver that binds with ApoA-I to allow for cholesterol drop off by HDL.

ABC Transporters

ATP Binding Cassette Transporters

Floppases that use ATP hydrolysis to power lipid export to the outer leaflet of the membrane

ABCA1: Expels cholesterol and phospholipids (phosphatidyl choline)

ABCG1: Expels cholesterol and sphingomyelin

Export of these transporters happens at the same time, they just deliver different materials. Forms nHDL, which is processed by LCAT to form mature HDL.

LCAT

Lechtin-cholesterol acyl transferase. Esterifies cholesterols in nHDL to cholesterol esters to form mature HDL.

ApoB-100

Apolipoprotein B-100

Binds to LDL in a 1:1 ratio, 4000 residue large monomeric protein that covers more than half of the surface.

Binds to LDL receptors to allow for endocytosis of LDLs and cholesterol delivery.

Clathrin Mediated Endocytosis

Clathrins are proteins that use ATP to pinch off the plasma membranes of cells. Forms a pit for the endocytosis of materials. In this context, LDLs bind to LDL Receptors using ApoB-100, which initiates endocytosis. The clathrins and LDL receptors are shuttled back to the surface in vesicles, while the LDL with ApoB-100 fuses with an acidic lysosome to initiate breakdown; produces fatty acids and cholesterol from lipids/cholesterol esters, and amino acids from ApoB-100.

ApoE

Apolipoprotein E

Associated with chylomicrons, VLDLs, and IDLs. Enhances binding to LDL receptors (higher affinity for ApoE than ApoB-100) and ApoE receptors, which allows for delivery of lipids in liver and CNS.

When IDL is repackaged into LDL, ApoE leaves and is replaced by ApoB-100.

How are ApoE defects associated with Alzheimer’s Disease?

ApoE allows export of lipids to CNS. Neurons require lipids to break down amyloid plaques; without lipids, these plaques build up and lead to neurodegeneration.