Digestion, Absorption, Transport, and Delivery of Lipids

Question 1

Digestion, Absorption, Transport, and Delivery of Lipids - What?

Answer 1

The digestion and absorption of dietary (exogenous) lipids involves emulsification using bile salts and breakdown - by hydrolytic enzymes - of these lipids and absorption of the digested products into the intestinal mucosal cells for packaging and transport to the necessary tissues

Transport of BOTH the digested lipid products as well as endogenous lipids through the body via the bloodstream REQUIRES various types of lipoprotein vesicles

Delivery of lipids from the lipoproteins to the various tissues for cellular use

Question 2

Digestion, Absorption, Transport, and Delivery of Lipids - Why?

Answer 2

Digestion/Absorption
The problem: lipids are insoluble in water, but hydrolytic enzymes are water-soluble enzymes

The solution: emulsify the lipid droplets and membranes using bile salts, which ahve amphipathic properties; this process increases the surface area of these lipid droplets to allow access to the digestive enzymes, which work at the interface of the droplet/aqueous surroundings

Transport/Delivery

The problem: again, lipids are insoluble in water, but the bloodstream and cell cytoplasm are primarily water

The solution: package the lipids (but exogenous and endogenous) into various types of micelles - called lipoprotein particles - which have a hydrophilic surface and a hydrophobic center containing the various types of lipids (chylomicrons, VLDL, LDL, and HDL)

Question 3

Digestion, Absorption, Transport, and Delivery of Lipids - Where?

Answer 3

Digestion: initial processing begins in the stomach, but most hydrolysis takes place in the small intestine

Absorption: digested products are absorbed into the intestinal mucosal cells (aka enterocytes)

Packaging and transport: the intestinal mucosal cells package the dietary lipid products into lipoprotein particle called chylomicrons; endogenous lipids are transported via other lipoprotein particles (VLDL, LDL, and HDL): VLDLs are produced in the liver & secreted directly to the bloodstream; LDLs are produced in the bloodstream as VLDLs become ‘modified’ as they circulate; HDLs are produced in the liver and intestine and secreted directly to the bloodstream

Delivery: lipids are delivered to various organs/peripheral tissues (excluding the brain)

Question 4

Digestion, Absorption, Transport, and Delivery of Lipids - How?

Answer 4

First: Digestion and Absorption

Second: Transport

Third: Delivery to tissues

Question 5

Where does the processing of dietary lipids begin?

Answer 5

Stomach

Primarily TAGs with short- or medium-chain length (<12C) are main target of gastric lipases

Question 6

Where does emulsification of dietary lipids occur? How does this occur?

Answer 6

Small Intestine

Bile is secreted by the liver or gallbladder (containing bile salts), which emulsifies the large lipid droplets into much smaller lipid droplets for access by the hydrolytic enzymes that are water-soluble

Question 7

What enzymes cause degradation of dietary lipids? What are they? What are their products?

Answer 7

Pancreatic enzymes

Pancreas secretes lipid hydrolytic enzymes into small intestine to digest: TAG, cholesterol esters, and phospholipids

Pancreatic Lipase - removes FAs from C1 and C3 (glycerol ‘end’ carbons)

Colipase - binds to the lipase for anchoring at the interface

Phospholipase A2 - removes FA from C2 of phospholipids

Products:

2-monoacylglycerols (from TAG breakdown)

lysophospholipids (from phospholipid breakdown)

free fatty acids (from both TAG and phospholipid breakdown)

free cholesterol (not esterified)

Question 8

What cells absorb the lipids? What are they encased in? What does that contain?

Answer 8

Intestinal mucosal cells (enterocytes) - absorb the lipids of the mixed micelles

Mixed micelles - cholic acid and other bile salts (help emulsify dietary lipids); products of digestion; cholesterol; lipid-soluble vitamins (from diet; absorbed, but not digested)

FAs <12C do not require mixed micelles for absorption by intestinal mucosal cells

Question 9

What kind of processing occurs after lipid digestion? Transport?

Answer 9

In mucosal cells

Cholate (other bile salts and bile acids) - sent back to liver (recycled)

TAGs, phospholipids, and cholesterol esters (the complex lipids) are resynthesized in ER

FAs <12C - bound to serum albumin; released to portal circulation for return to liver

Packaging for export:

Newly synthesized TAGs, cholesterol esters, etc - very hydrophobic, insoluble

Packaged in lipoprotein particles called chylomicrons (water-soluble form of lipid droplets) - for transport to necessary tissues

Chylomicrons are released by exocytosis from mucosal cells

Question 10

What do transport lipoproteins do? What are the classes of transport lipoproteins?

Answer 10

Both exogenous and endogenous lipids are transported

transport lipids in the blood:

Classes:

Chylomicrons

VLDL: very low density lipoproteins

IDL: intermediate-dense lipoproteins (VLDL remnants)

LDL: low density lipoproteins

HDL: high density lipoproteins

Lipoprotein (a) [lp(a)] - nearly identical to LDL particle

Question 11

What are the general features of transport lipoproteins?

Answer 11

Surface layers = amphipathic monolayer consisting of: phospholipids, cholesterol, apolipoproteins (aka apoproteins)

Interior = hydrophobic, containing: TAG, cholesterl (cholesteryl) esters

Question 12

Explain cholesterol ester synthesis and why it is important.

Answer 12

FA attached (ester bond) to -OH group of cholesterol

LDL - uses ACAT (acyl CoA:cholesterol acyltransferase): attaches a fatty acid (from FA-CoA derivative) to cholesterol, which is then stored in lipoprotein particle

HDL - uses LCAT (lecithin:cholesterol acyltransferase): lecithen = phosphatidylcholine; cholesterol taken up by HDL are immediately esterified by transferring the FA from C2 of PC to cholesterol

Importance: cholesterol now completely hydrophobic and in interior of lipoprotein for safe packaging/transport

Question 13

What are the characteristics of major classes of human plasma lipoproteins?

Answer 13

From chylomicrons & remnants -> VLDL -> IDL -> LDL -> HDL :

density increases

particle diameter decreases

Major lipids:

chylomicrons & remnants = dietary TAGs

VLDL = endogenous TAGs, cholesterol esters, cholesterol

IDL = cholesterol esters, cholesterol, TAGs

LDL = cholesetrol esters, cholesterol, TAGs

HDL = cholesterol esters, cholesterol

Question 14

What are the major apolipoproteins?

Answer 14

apo B-100: LDL, VLDL, IDL - synthesized in liver; Ligand for LDL receptor

apo C-II: VLDL, HDL, chylomicrons; activator of extrahepatic lipoprotein lipase

apo E: VLDL, IDL, HDL, chylomicrons, chylomicron remnants; Ligand for chylomicron remnant receptor in liver and VLDL receptor (may play a role in Alzheimer’s Disease)

Question 15

Summarize Chylomicrons - Key apoproteins? Synthesized? Transports? Transports from? Delivers to? Result?

Answer 15

Key Apoproteins: C-II; E

Synthesized: intestinal mucosal cells

Transports: DIETARY TAG, C, CE, PL, lipid soluble vitamins

Transports from: intestine

Delivers to: Tissues - the FAs from the TAGs via lipoprotein lipase (with apo C-II)

Result: ~90% of TAGs are removed

Question 16

Summarize VLDL - Key apoproteins? Synthesized? Transports? Transports from? Delivers to? Result?

Answer 16

Key Apoproteins: B-100; C-II; E

Synthesized: liver

Transports: ENDOGENOUS TAG, C, CE, PL

Transports from: liver

Delivers to: Tissues - the FAs from the TAGs via lipoprotein lipase (with apo C-II)

Result: most of the TAGs are removed - VLDL remnants are IDLs

Question 17

Summarize IDL - Key apoproteins? Synthesized? Transports? Transports from? Delivers to? Result?

Answer 17

Key Apoproteins: B-100; E

Synthesized: in plasma- remnants of VLDLs after TAG removal

Transports: C and CE

Transports from: Liver (as VLDL) and plasma

Delivers to: Endocytosed by liver or become LDLs if stay in plasma

Result: contain mostly CE in interior

Question 18

Summarize LDL - Key apoproteins? Synthesized? Transports? Transports from? Delivers to? Result?

Answer 18

Key Apoproteins: B-100 only

Synthesized: in plasma - from VLDL -> IDL -> LDL

Transports: C and CE; primary function of LDLs is to provide C to the peripheral tissues (or may return it to the liver)

Transports from: liver (as VLDL) and plasma

Delivers to: endocytosed by ALL TISSUES (except brain) via LDL receptors for B-100 (ligand)

Result: LDL = ‘bad’ cholesterol because all tissues can take up these particles for acquiring cholesterol

Question 19

Summarize HDL - Key apoproteins? Synthesized? Transports? Transports from? Delivers to? Result?

Answer 19

Key Apoproteins: A-I; D

Synthesized: Liver (precursor) and intestine

Transports: C and CE (‘scavenger’ of C from membranes of cells or other lipoprotein particles)

Transports from: tissues; plasma

Delivers to: LIVER (note: only means of excreting C is as bile salts via the liver)

Result: HDL = ‘good’ cholesterol because scavenges cholesterol from tissues for return to live rand possible excretion from body

Question 20

Summarize lipoprotein (a) - Synthesized? Key apoproteins? Result?

Answer 20

Synthesized: liver

Apoproteins: like LDL, but contains both apo B-100 and apo(a) [resembles plasminogen; interferes with plaque dissolution]

Result: increases plaque formation (inhibits blood clot dissolution); responsible for ~25% of heart attacks for people under 60

Question 21

What is the pathway of lipid transport of dietary lipids (metabolism of chylomicrons)?

Answer 21

Exogenous dietary lipids

Question 22

What is the pathway of lipid transport for endogenous lipids (metabolism of VLDL and LDL)?

Question 23

Describe triacylgycerol delivery to tissues.

Answer 23

Extracellular lipoprotein lipase - cleaves off free FAs from TAG in chylomicrons and VLDL

• an extracellular enzyme anchored by heparin sulfate to capillary walls of most tissues (but mainly adipose, cardiac, and skeletal muscle tissues)

Fatty acids - taken up by tissues (i.e. adipose tissue); glycerol is returned to liver

Question 24

Describe the regulation of TAG metabolism by Lipoprotein Lipase (LPL) - Location//Acts on? Function? Regulation?

Answer 24

Location//Acts on: Capillary//Chylomicrons, or VLDL, TAG core

Function: converts (cleaves) TAG to fatty acids to be absorbed by tissues

Regulation: Apoprotein C-II

Question 25

Describe the regulation of TAG metabolism by Hormone Sensitive Lipase (HSL) - Location//Acts on? Function? Regulation?

Answer 25

Location//Acts on: Adipose tissue//stored fat

Function: mobilizes TAG to release FAs in circulation

Regulation: Glucagon (+); Epinephrine (+); Insulin (-)

Question 26

Describe the regulation of TAG metabolism by Pancreatic Lipase - Location//Acts on? Function? Regulation?

Answer 26

Location//Acts on: intestines, excreted by pancreas//dietary fat

Function: digests dietary TAG to monoacylglycerol + free FAs

Regulation: co-lipase (+

Question 27

Describe endocytosis of lipid particles

Answer 27

LDLs (all tissues except brain); chylomicron remnants (liver only); IDLs (liver only); HDLs (liver only)

the ENTIRE lipoprotein particle is taken up by a cell

Question 28

Using LDL as an example, describe the process of endocytosis of lipoproteins

Answer 28

LDL Receptor-mediated endocytosis (i.e. clarthrin-dependent)

LDL primary function: provide cholesterol to peripheral tissues [or return it to liver]

LDL receptors (bind ApoB-100) - clustered in pits on membranes

Clathrin - protein on intracellular side of pit

Once LDL vesicle inside - loses clathrin coat and fuses with similar vesicles to form larger vesicles called endosomes

Contents of LDL degraded and released into cell

Question 29

Describe the effects of endocytosed cholesterol on cellular cholesterol homeostasis

Answer 29

HMG-CoA reductase: high [cholesterol] - inhibits

de novo cholesterol synthesis - decreases

New LDL receptor protein synthesis - reduced (limits further entry of LDL cholesterol into cells)

Question 30

Diagram the Cellular Uptake and Degradation of LDL via endocytosis

Question 31

Clinical Problems associated with lipid digestion, absorption, and transport - Lipid Malabsorption

Answer 31

Increased lipids (even lipid-soluble vitamins) in the feces

Cause: disturbances in lipid digestion/absorption (i.e. cystic fibrosis, shortened bowel)

Question 32

Clinical Problems associated with lipid digestion, absorption, and transport - Heart Disease

Answer 32

recall lipoprotein (a) - inhibits blood clot dissolution

Question 33

Clinical Problems associated with lipid digestion, absorption, and transport - Hypercholesterolemias

Answer 33

High plasma levels of cholesterol

20% of population has defective regulation of cholesterol synthesis

Defect in cholesterol uptake into cells:

• most often due to defective LDL receptor [could also be due to a ligand defect (apo B-100), but more rare cause]
• solution: inhibition of cholesterol synthesis

Drugs like the statins (simvastatin, lovastatin, and mevastatin): structural analogs of HMG-CoA - thus competitive inhibitors of HMG-CoA reductase

Question 34

Hypercholesterolemias - Familial Hypercholesterolemia

Answer 34

Genetic cause = defective LDL receptor synthesis

IDL not taken back up to liver, LDL stuck in blood

Diet: lower cholesterol, fat

Drugs: inhibit cholesterol synthesis (statins)

Resin: increase excretion

Question 35

Hypercholesterolemias - High cholesterol diet

Answer 35

Increase in dietary cholesterol -> cholesterol repression of LDL receptor synthesis -> LDL reuptake taken back into liver, LDLs stuck in tissues

Diet: lower fat/cholesterol - increase unsaturated w-3 fats; - antioxidants

increase fiber (resin)

Question 36

Describe dyslipidemia

Answer 36

Definition: elevated TAGs (in chylomicrons/VLDLs) and low high-density lipoproteins (HDL) levels

Question 37

Describe dyslipidemia and how it relates to Diabetes

Answer 37

lipoprotein lipase activity (LPL) is low in adipose tissue (particularly) and in muscle [note: lipoprotein lipase activity is stimulated by insulin - particularly in adipose tissue by causing increased secreted of LPL to the extracellular surface]

Result: hypertriacylglycerolemia, which is increased plasma amounts of chylomicrons and VLDLs (carrying exogenous and endogenous TAGs, respectively)

Question 38

Describe dyslipidemia and how it relates to metabolic syndrome

Answer 38

Metabolic syndrome: (aka abdominal obesity)

• associated with a cluster of metabolic abnormalities
• including: glucose intolerance, insulin resistance, hyperinsulinemia, dyslipidemia, and hypertension
• dyslipidemia associated with metabolic syndrome is by far the most common lipid disorder in the US

Question 39

Diagram the intertissue relationships in type 2 diabetes - leading to hypertriacylglycerolemia