Digestion, Absorption, Transport, and Delivery of Lipids Flashcards
Digestion, Absorption, Transport, and Delivery of Lipids - What?
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
Digestion, Absorption, Transport, and Delivery of Lipids - Why?
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)
Digestion, Absorption, Transport, and Delivery of Lipids - Where?
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)
Digestion, Absorption, Transport, and Delivery of Lipids - How?
First: Digestion and Absorption
Second: Transport
Third: Delivery to tissues
Where does the processing of dietary lipids begin?
Stomach
Primarily TAGs with short- or medium-chain length (<12C) are main target of gastric lipases
Where does emulsification of dietary lipids occur? How does this occur?
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
What enzymes cause degradation of dietary lipids? What are they? What are their products?
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)
What cells absorb the lipids? What are they encased in? What does that contain?
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
What kind of processing occurs after lipid digestion? Transport?
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
What do transport lipoproteins do? What are the classes of transport lipoproteins?
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
What are the general features of transport lipoproteins?
Surface layers = amphipathic monolayer consisting of: phospholipids, cholesterol, apolipoproteins (aka apoproteins)
Interior = hydrophobic, containing: TAG, cholesterl (cholesteryl) esters
Explain cholesterol ester synthesis and why it is important.
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
What are the characteristics of major classes of human plasma lipoproteins?
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
What are the major apolipoproteins?
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)
Summarize Chylomicrons - Key apoproteins? Synthesized? Transports? Transports from? Delivers to? Result?
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
Summarize VLDL - Key apoproteins? Synthesized? Transports? Transports from? Delivers to? Result?
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
Summarize IDL - Key apoproteins? Synthesized? Transports? Transports from? Delivers to? Result?
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
Summarize LDL - Key apoproteins? Synthesized? Transports? Transports from? Delivers to? Result?
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
Summarize HDL - Key apoproteins? Synthesized? Transports? Transports from? Delivers to? Result?
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
Summarize lipoprotein (a) - Synthesized? Key apoproteins? Result?
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
What is the pathway of lipid transport of dietary lipids (metabolism of chylomicrons)?
Exogenous dietary lipids
What is the pathway of lipid transport for endogenous lipids (metabolism of VLDL and LDL)?
Describe triacylgycerol delivery to tissues.
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
Describe the regulation of TAG metabolism by Lipoprotein Lipase (LPL) - Location//Acts on? Function? Regulation?
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
Describe the regulation of TAG metabolism by Hormone Sensitive Lipase (HSL) - Location//Acts on? Function? Regulation?
Location//Acts on: Adipose tissue//stored fat
Function: mobilizes TAG to release FAs in circulation
Regulation: Glucagon (+); Epinephrine (+); Insulin (-)
Describe the regulation of TAG metabolism by Pancreatic Lipase - Location//Acts on? Function? Regulation?
Location//Acts on: intestines, excreted by pancreas//dietary fat
Function: digests dietary TAG to monoacylglycerol + free FAs
Regulation: co-lipase (+
Describe endocytosis of lipid particles
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
Using LDL as an example, describe the process of endocytosis of lipoproteins
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
Describe the effects of endocytosed cholesterol on cellular cholesterol homeostasis
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)
Diagram the Cellular Uptake and Degradation of LDL via endocytosis
Clinical Problems associated with lipid digestion, absorption, and transport - Lipid Malabsorption
Increased lipids (even lipid-soluble vitamins) in the feces
Cause: disturbances in lipid digestion/absorption (i.e. cystic fibrosis, shortened bowel)
Clinical Problems associated with lipid digestion, absorption, and transport - Heart Disease
recall lipoprotein (a) - inhibits blood clot dissolution
Clinical Problems associated with lipid digestion, absorption, and transport - Hypercholesterolemias
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
Hypercholesterolemias - Familial Hypercholesterolemia
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
Hypercholesterolemias - High cholesterol diet
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)
Describe dyslipidemia
Definition: elevated TAGs (in chylomicrons/VLDLs) and low high-density lipoproteins (HDL) levels
Describe dyslipidemia and how it relates to Diabetes
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)
Describe dyslipidemia and how it relates to metabolic syndrome
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
Diagram the intertissue relationships in type 2 diabetes - leading to hypertriacylglycerolemia
