XIAO Flashcards
1
Q
lipoprotein lipase
A
enzyme that metabolizes lipoprotein components
- converts VLDL to IDL to LDL
2
Q
3 major lipid categories
A
- triacylglycerol (triglyceride)
- cholesterol, cholesteryl ester (esterified cholesterol, fatty acid chain attached to cholesterol)
- phospholipids
3
Q
lipid classification based on function
A
1) storage: fatty acids, triglycerides, sterols
2) structural: phospholipids (phosphatidylcholine, phosphatidylinositol, phosphatidylserine, sphingolipids)
3) associated molecules: lipoproteins (VLDL-C, LDL-C, IDL-C, HDL-C, chylomicron)
4
Q
lipid classification based on roles in CV disease
A
- enhancers: triglycerides, trans fatty acids
- conditionally impact on CVD’s: HDL (good cholesterol), fatty acids
5
Q
lipoprotein
A
carry lipids (TG, cholesterol, phospholipids) in blood
6
Q
lipoprotein structure
A
- neutral lipid core (TG and CE (cholesterol is carried by lipoprotein converted to cholesteryl ester)
membrane:
- phospholipid outer layer
- some free cholesterol (most carried in the form of cholesteryl ester)
- structural proteins (apolipoproteins depending on specific type of lipoprotein)
- non-structural proteins that attach and detach - (C-II and C-III regulate lipoprotein lipase) regulate lipoprotein metabolism, anti inflammatory proteins in HDL
7
Q
lipoprotein classes
A
Based on density - lipoproteins carry different proportions of lipids (lighter) and proteins (heavier)
- HDL carries more proteins
- VLDL carries more lipids (metabolized to lose some lipids to become IDL and then LDL (become smaller and heavier (more dense))
8
Q
Chylomicrons
A
made by the gut - formed right after we eat fatty food - dietary fat used to from chylomicrons - carrier of exogenous lipids
9
Q
VLDL
A
made and processed in the liver (carrier for endogenous lipids)
10
Q
Majority of TG lost when hydrolyzed, CE stays
A
true
11
Q
______ and ______ carry the most TG
A
chylomicrons (most) and VLDL
12
Q
major apolipoprotein in chylomicrons
A
B-48
13
Q
major apolipoprotein in VLDL, IDL, LDL
A
B-100
14
Q
major apolipoprotein in HDL
A
A-I
15
Q
major cholesterol carrier in the form of CE
A
LDL (you lose triglycerides not CE when metabolized)
16
Q
chylomicron function
A
Transport of dietary exogenous core substances from intestine to tissues
17
Q
VLDL, IDL, LDL function
A
transport of endogenous core substances from liver to tissues
18
Q
HDL function
A
transport of endogenous cholesterol from the tissues to the liver
19
Q
lipemic sample
A
blood sample high in fat (due to disease/ following a fatty meal)
20
Q
blood sample after centrifugation
A
- chylomicrons at the top (least dense)
21
Q
lipoprotein separation and identification
A
1) electrophoresis (based on size and charge): chylomicrons are huge and don’t migrate (stay near the -ve end)
2) ultracentrifugation (based on density): chylo at the top (least density)
22
Q
lipolysis and conversion
A
- Reduce size; lose/gain (exchange) apo proteins
- VLDL to IDL to LDL
- Chylomicron to chylomicron remnant
- HDL to HDL remnant
23
Q
lipoprotein lipase (LPL)
A
- found on the endothelial cell surface
- key enzyme for VLDL to LDL + chylomicron to chylomicron remnant
- regulation through protein abundance or function
- LPL function enhanced by: APOC2, APOA5, GPIHBP1 (tethers), LMF1
- LPL function impaired by: APOC3, ANGPTL3, ANGPTL4
24
Q
Hepatic lipase (HL)
A
main enzyme for conversion of HDL to HDL remnant
25
endothelial lipase (EL)
preferred substrate: phospholipids
26
Atherogenic Dyslipidemia Complex
- causes atherosclerotic cardiovascular disease (ASCVD)
- poor metabolism of TG rich lipoprotein (chylomicron and VLDL) - imbalance between production and clearance - accumulation in blood
- due to environment (lifestyles, medications, pregnancy, medical conditions) or genetics (mutations)
27
How does dietary lipid overload contribute to metabolic diseases?
- Energy-dense, high-fat diet → Increased lipid absorption and intestinal lipid retention → IBD and colorectal cancer
- Increased adiposity → Obesity:
- IBD and colorectal cancer
- NAFLD and atherosclerosis
- decreased insulin sensitivity and glucose tolerance → Type 2 Diabetes
28
Dietary fat digestion and absorption
TG
- digestion: lingual, gastric, pancreatic (SI) lipase
- digestion products: monoacylglycerol and fatty acids
- uptake into enterocyte of intestine: passive (through concentration gradient) and facilitated transport (through CD36 and FATP4 (fatty acid transport protein 4))
- re-esterification at ER: monoacylglycerol acyltransferases (MGAT), diacylglycerol acyltransferase (DGAT)
- formation of lipid droplets in ER
- MTP adds apoB48 to lipid droplet to make pre-chylomicron (sent to golgi --> modified to mature chylomicron, which exocytoses from basolateral membrane and enters the lymph)
OR
- lipid droplet goes into cytoplasm and becomes CLD (cytoplasmic lipid droplet)
29
TG metabolic fates
- chylomicron synthesis and secretion
- beta-oxidation in mitochondria (energy generation)
- CLD storage
- synthesis of other complex lipids (phospholipids)
30
Proteins used by TG for facilitated transport
CD36 and fatty acid transport protein 4 (FATP4)
31
pancreatic lipase
pancreatic lipase breaks down TAGs into fatty acids and 2-MAGs in the lumen of the small intestine (get reesterified by MAG/phosphatidic in the enterocyte)
32
2 ways for TGs to be reesterified in the enterocyte
1) MAG pathway (major - 80%)
2) phosphatidic-acid pathway (glucose --> glycerol-3-phosphate --> lysophosphatidic acid --> phosphatidic acid --> DAG --> TAG)
33
chylomicron synthesis
- only long chain fatty acids (LCFA)
- LCFA re-esterified into TGs (can become chylomicrons or CLD)
- diameter 250 nm (75-1200nm - depending on diet)
- apolipoproteins added to LDs in ER
- uptake into golgi for chylomicron maturation
- made of TG (primarily), phospholipids, cholesteryl esters, free cholesterol, apolipoproteins
- apolipoproteins: B48 added in the ER; A1 and A4 added in the golgi
- exocytosed from the basolateral membrane
- secreted into lacteals, transported in lymphatics
- one B-48 / chylomicron particle
- MTP (microsomal triglyceride transfer protein) adds B-48 to LD to form chylomicron
- PCTV (pro-chylo transport vesicle) - transports from ER to golgi
- apolipoproteins made in the RER
34
Short chain fatty acids (SCFA)
Medium chain fatty acids (MCFA)
don't need to be re-esterified - water soluble - can be directly transported to portal blood (don't go through chylomicron synthesis pathway ) - once they leave the cell , go to blood vessel and get transported to the liver through the portal vein
35
chylomicron post-enterocyte transport
- chylomicron is secreted into the intercellular space and goes into the lamina propria
- go into LACTEAL (lymphatic vessels; single lumen, blind ended (not a separate structure), at the center of each intestinal villus
- uptake: mostly paracellular; openings (flaps) on lacteal wall to chylomicrons to start - open/close (button/zipper) states
- lymphatic function: pumping (tonic and phasic contractions and valves to prevent backflow - unidirectional movement of lymph fluid)
36
lymphatic vasculature
- lacteal
- collecting lymph duct
- thoracic duct
- venous circulation at the left subclavian vein
- in the gut, lipoproteins and chylomicrons circulating in the lymph duct go to thoracic duct and then lymph fluid joins venous blood there - takes some time to show up in the blood (so as to not overwhelm muscles by sudden massive supplies of lipids)
37
cytoplasmic lipid droplet
- have TAGs and associated proteins
- # and size increase with fat ingestion and decrease at fasting (feeding-fasting dynamic)
- transient lipid storage - go through lipolysis to release fatty acids (can be beta-oxidized or used for chylomicron synthesis)
- autophagy (lipophagy)
- DGAT 2 imp in CLD formation
38
cholesterol transporters
- NPC1L1 (Niemann-Pick C1-like 1) - major
- SR-B1 (scavenger receptor class B type I)
39
intestinal cholesterol uptake and transport
- directly absorbed through transporters: NPC1L1 (Niemann-Pick C1-like 1) and SR-B1 (scavenger receptor class B type I)
- most cholesterol taken up by the intestine is secreted in chylomicrons
- chylomicron-cholesterol is taken up by the liver for biliary excretion into feces
40
Transintestinal cholesterol excretion (TICE)
- cholesterol goes into enterocytes through transporters on the basolateral membrane --> goes into lumen --> secreted into feces
- choles is derived from the plasma and taken up by the basolateral side of the enterocytes
- excrete to intestinal lumen, via intestinal sterol transporters ATP-binding cassette subfamily G member 5 (ABCG5) and ABCG8
- contributes to fecal cholesterol
41
- cholestyramine
- colestipol
- colesevelam
compounds that bind to bile acid (made of cholesterol) and stay in the gut so cholesterol can't be transported across apical membrane - eventually secreted in feces - liver has to make brand new bile acids, using up new cholesterol (decreases the levels)
42
orlistat
- lipase inhibitor
- inhibit digestion of CE and stuff
43
Ezetimibe
- NPC1L1 inhibitor
- cholesterol not absorbed across apical membrane
44
Lomitapide JTT-130
inhibits MTP
45
JTP-103237
MGAT inhibitor
46
PF-04620110
DGAT inhibitor
47
role of liver in lipid homeostasis
- synthesizes and secretes VLDL
- cholesterol synthesis
- bile acids synthesis and secretion
- major tissue for LDL uptake (40-60%)
