Block 3 Lipid Absorption & Transport Flashcards
What are the major dietary lipids?
TGs, C, CE (chol esters), PL, FFA
Where does metabolism of dietary lipids happen?
Proteolytic digestion in small int lumen
Absorption into enterocytes
Re-synthesis of major lipid classes in enterocytes
Transport in lymph, blood
Utilization by peripheral tissues & storage by adipose tissue
What kind of degradation happens in stomach, duodenum, and jejunum?
St: lingual & gastric lipases (infants)
Duo: Emulsification (chemical by bile salts, mechanical by peristalsis)
Jej: Proteolysis (panc enzymes)
How do TG, PL, CE, and FA change from mouth to stomach to small intestine?
Highly hydrophobic to stomach (TG limited and <C12, FA limited); in SI, hydrophilic mixed micelles
What form do TG, PL, CE, and FA take in the small intestine?
TG: 2-MAG + FA
PL: glycerylphosphorylbase
CE: cholesterol + FA
FA: FA
What are bile salts?
Amphipathic molecules that increase SA/V ratio for interaction with lipases
What are lipases?
Carboxylesterases acting on long chain acylglycerols, act at lipid/water interface
What lipases act on exogenous and endogenous lipids?
Exo: pancreatic (& lingual, stomach, mucosal, some phospholipase)
Endo: lipoprotein, hepatic, hormone-sensitive (& some phospholipase)
How are TAGs degraded by pancreatic lipase?
Removes FA of all chains lengths at C1,3. Colipase reduces surface tension to stabilize. Product: MAGs & FAs stabilized by bile salts.
How are cholesteryl esters degraded by esterase?
Hydrolyzed by pancreatic cholesteryl ester hydrolase (cholesterol esterase) –> free chol and FA
How are phospholipids degraded by phospholipase?
PLA2 from pancreas activated in int lumen by trypsin. Removes FA at C2 -> lysoPL. Lyso-PLase removes FA at C1 -> glycerylphosphorylbase for excretion or degradation/absorption
Where is the main site of absorption of mixed micelles? What happens to bile salts?
Brush border membrane of enterocytes; BS remains in gut, extensively reabsorbed in ileum (95%)
Where are micelles of short and medium chain FFA absorbed?
They don’t need micelles for absorption
What is DGAT?
Diglycerol acyltransferase converts passively diffused 2 FA + monoglyceride -> TG
How is cholesterol absorbed in enterocyte?
Taken up by NPC1L1-R, pumped out of cell by ABCG5/G8. *Same transporters for non-chol plant sterols
What’s the difference in absorption of chol and non-chol sterols & why?
Chol: 50-60% absorbed
Non: 1-5% absorbed
ABCG5/G8 transporter more efficient with non-chol sterols
What happens to the cholesterol that isn’t pumped back out through ABCG5/G8?
Esterified by acyl-coenzyme cholesterol acyl-transferase (ACAT) into cholesteryl esters
What are the major approaches to reduce cholesterol absorption?
Increase dietary intake plant sterols (stanols/phytosterols, Benecol) or antagonize NPC1L1 transporter (Ezetimibe/Zetia)
What is lipid malabsorption?
Loss of lipids (including lipo-soluble vitamins & essential FAs); steatorrhea; perhaps reduced bile acids synthesis, secretion deficit of panc enzymes, defective enterocytes
How are TG and CE resynthesized in the enterocyte?
Acyltransferases specific to chol and TG; use activated LCFFA for esterification (act by fatty acyl CoA synthetase/thiokinase)
How are SCFA and MCFA secreted from intestinal cells? Cholesterol, FFA, acyglycerols, & partly hydrolyzed PLs?
SC/MC: bind to albumin, secreted into portal circulation, transported to liver
Other lipids: chylomicrons -> lymph
What is a lipoprotein?
Macromolecular complex of different lipids and apolipoproteins; surface Apo & PLs, intermediate free chol, core of TG and CE
What is transported by chylomicrons, VLDL, LDL, and HDL?
Ch: exogenous TG
VLDL: endogenous TG
LDL: endo chol (liver to peripheral tissues)
HDL: endo chol (per to liver)
How does size, density, and lipid/protein ratio change among the 4 classes of LPs?
Chylos are biggest, least dense, with highest L/P ratio. HDLs are smallest, densest, and lowest L/P ratio.
How does affinity for LPL, density, and atherogenicity ratio differ among the 4 classes of LDL?
LDL 1 is least dense, with highest affinity for LPL and least atherogenicity. LDL 4 is the opposite.
What are the functions of apolipoproteins?
Bind and emulsify lipids, ligands for Apo receptors involved in lipid uptake (ApoE,B), cofactors for enzymes involved in lipoprotein metabolism (Apo A-1, C-2)
What are the following apolipoproteins associated with and what are their functions: B48, B100, C2, C3, E, A1?
B48: chyl for assembly, exocytosis chylos
B100: VLDL, IDL, LDL to bind LDL-R
C2: chyl, VLDL, IDL, HDL to activate LPL
C3: chyl, VLDL, IDL, HDL to inhibit LPL
E: chyl, remnant, VLDL, IDL, HDL to bind LDL-R
A1: HDL to activate LCAT
Where are chylomicrons assembled? What happens with a lack of ApoB48?
Lipids in SER, proteins in RER. Assembly in Golgi; secreted in lymph by exocytosis; B48 deficit -> TG accumulation in intestinal cells (congenital abetalipoproteinemia)
What is MTP (microsomal transfer protein)?
Involved in lipid then TG transfer to ApoB48 and maturation of chylos. Also involved in lipidation of ApoB100 and assembling VLDL in liver.
How do chylomicrons mature?
While circulating in blood and lymph, they acquire ApoC2 and ApoE from HDLs
What do ApoC2 and ApoE do?
C2: assists degradation of TG by lipoprotein lipase
E: recognized by receptors in liver and help remove partially digested chylos from bloodstream
What enzyme is responsible for TG hydrolysis in capillaries?
Lipoprotein lipase
Where is Lp lipase synthesized, and how is it transported?
Synth in adipose, muscle (cardiac), lactating mammary glands; transported on surface of capillary endothelium anchored via heparin sulfate PGs
How do apoC2 and C3 affect Lp lipase? ApoE?
C2 required for activity, C3 inhibits activity; ApoE assists clearance of chylomicron remnants (lack -> familial type 3 hyperlipoproteinemia)
What are the products of lipoprotein lipase activity?
Releases 3 FA from TG. Glycerol -> Gly-3-P in liver, FA -> adipose/mm, chylo -> remnants
How are mm and adipose LPL different?
Isoenzymes; mm (cardiac): low Km, unaltered in fed state, increased/unaltered in fasted/exercise
Adipose: high Km, increased in fed state (insulin), no effect in fasted state
What are the major steps of TG synthesis? Where are they stored?
Generation of glycerol backbone from glucose, activation FFA, synthesis of TG; adipocyte and hepatocyte
What enzyme is missing in adipose that is present in liver? How is Gly3P made then?
Glycerol kinase (gly -> Gly3P) Glucose -> DHAP + NADH -> Gly-3P
How is Gly-3P modified to make TAG?
Gly3P + 2 FACoA -> phosphatidic acid - Pi -> DAG + FACoA -> TAG
How does fat accumulation differ in fed and post-absorptive states?
In fed state, insulin upregulates adipose LPL on cap endo & GLUT-4. Post-ab: low insulin = lower LPL, downregulated GLUT-4. Most FA bound to albumin for B-ox
How are VLDL TGs synthesized?
In liver, glycerol kinase converts glycerol to Gly3P; glucose -> DHAP -> Gly-3P -> PA (Gly3P PAT & Acyl-3P AT) -> TG (Pase & DGAT)
What enzymes are important for final step of CE and TG synthesis in liver?
CE: ACAT
TG: DGAT
What is MTTP?
Microsomal TG transfer protein in liver ER lumen helps assemble VLDL & transfer lipids to ApoB100 while being translocated into ER during translation
How does VLDL change as it is secreted from liver and cleared from circulation?
Released with ApoB100 and ApoA1, + C2 and E from HDL, exchanges lipids with HDL (cat by CETP). ⅔ cleared by liver, ⅓ hydrolyzed by LPL (becomes IDL)
What stimulates VLDL synthesis by the liver?
Excessive consumption calories, alcohol, carbs; high concentration FFA reaching liver
What do LDLs do, and how are they made?
Major delivery route for cholesterol (endocytosis by LDL-R) & major plasma chol carrier (high chol & CE) & atherogenic LP, formed by sequential hydrolysis VLDL by LPL, contains only ApoB100
Where is HDL produced? ApoA1 and A2?
HDL: liver & intestine (coalescence of individual PL-Apo complexes)
A1: liver & intestine
A2: liver only
What are the major potential targets for atherosclerosis therapies?
HDL-assc apo: ApoA1 & E
HDL-modifying plasma enzymes & transfer proteins: LCAT, CETP, LPL, hepatic lipase
Cellular/cell-surface proteins influencing HDL metabolism: ABCA1, ABCG1, SR-B1
What is the function of HDL?
Major cholesterol carrier from peripheral tissues back to liver
What are lipid poor ApoA1 (pre-HDL), nascent (pre-beta) HDL, and mature (alpha) HDL?
Lipid poor: smallest HDL with little PL, no chol
Nascent: produced after free chol acquired from per tissues
Alpha: following chol esterification by LCAT & exchange of CE for TG with VLDL, LDL (by CETP), can acquire more free chol from per tissues
What is CETP?
Exchanges CE from HDL for TG from VLDL/LDL (ApoB-containing)
What is hepatic lipase?
Hydrolyzes TG to convert HDL2 to HDL3 (CE enriched, smaller), which can be cleared by the kidney
What are desirable LDL/HDL ratio and cholesterol levels in mg/dl?
Low LDL/HDL protective against coronary heart disease, Total/HDL >4.5 risk factor
Desired: total chol 60
What lipid levels indicate diabetic dyslipidemia?
High TG, LDL & low HDL
What are the goal ApoB levels for highest-risk and high-risk patients with CMR and lipoprotein abnormalities?
Highest: ApoB <80
