Lipid Uptake Part 1 Flashcards
How does the body deal with the biochemical problem of lipids having low solubility?
- solubilize with detergents (bile salts)
- associate with proteins for transport (chylomicrons, VLDL, LDL, HDL)
what are the 3 important lipases for lipids?
- hormone sensitive lipase
- pancreatic lipase
- lipoprotein lipase
function of hormone sensitive lipase?
mobilizes TAGs from adipose tissue
function of pancreatic lipase?
digestion of TAGs - converts triacylglycerol -> fatty acids and monoacylglycerol
How does the weight loss drug orlistat/xenical/alli work?
reversibly inhibits activity of pancreatic lipase -> prevents absorption of triglycerides
side effects of orlistat/xenical/alli?
reduce absorption of fat-soluble vitamins (A,D,E,K), beta-carotene, fatty acids, 2-monoacylglycerol
cholic acid
a bile salt w/ ring structure of cholesterol but has more hydroxyls, a polar side chain, and lacks C5-6 db
where are bile salts made?
made in liver -> then transferred to gall bladder and released to intestine
how much of bile salts are recycled to liver?
95%
what is cholestryamine/cholybar/questran?
bile acid sequestrant - binds negatively charged bile and prevents reabsorption
what is cholestryamine/cholybar/questran used to treat?
hypercholesterolemia and the itching caused by liver disease and failure to process bile
chemical description of cholestyramine
positively charged resin, not soluble in water
what does the use of cholestryamine stimulate in the body?
it removes bile acids, which stimulates liver bile acid synthesis from cholesterol -> stimulates LDL receptor in liver, causing reduced serum cholesterol
what does the action of cholestryamine depend on?
dose administered
gall bladder problems present how to patients?
trouble digesting high fat meal, upper right quadrant abdomen pain
what does the pancreas secrete to aid in absorption of fat?
bicarbonate, lipase, colipase
what induces secretion of pancreatic enzymes?
gut hormone cholecystokinin
absorption of fats pathway
ingest fat -> bile salts bind TGs -> lipase/colipase break TGs down to FA + 2-MG -> bile salts take 2-MG and FA into enterocytes -> remade into TG -> packaged into chylomicrons -> travel through lymph back to blood/ bile salts recycled to liver
absorption of medium and short chain FAs
do not need micelles! enter portal blood rather than lymph - travel in blood bound to serum album
absorption of long and very long chain FAs
packed into mixed micelles prior to absorption by microvilli on surface of intestinal epithelial cells - reassembled into TGs -> chylomicrons through lymph to blood
what do long and very long chain FA chylomicrons pick up in the blood?
apoCII and apoE
how are TAGs digested?
lipoprotein lipase (LPL) on capillaries
synthesis of chylomicrons
TGs from sER and ApoB-48 from rER combined in golgi, which secretes nascent chylomicrons that are exocytosed to lymph and travel through lymph to blood
what do chylomicrons contain?
TAGs, apoproteins, other lipids (cholesterol esters)
where are chylomicrons produced?
intestinal epithelia from dietary fat
VLDL: where produced, function
produced in liver mainly from dietary CHO - carries TGs in blood
IDL
VLDL remnant produced in blood
what happens to IDL after TG digestion?
endocytosed by liver or converted to LDL
LDL
remnant of IDL after TG digestion, VLDL end product: contains lots of cholesterol and cholesterol esters
what is the fate LDL in blood?
endocytosed by liver and peripheral tissues
where are LDLs produced?
in blood
where are HDLs produced?
liver and intestine
HDL fxn
exchanges proteins and lipids for other lipoproteins - returns cholesterol from peripheral tissues to liver
which human plasma lipoprotein is most dense and which is least dense?
most dense: HDL
least dense: chylomicron
% weight of protein and TG in chylomicrons
protein: 2
TG: 88
% weight of protein and TG in VLDL
protein: 10
TG: 54
% weight of protein and TG in LDL
protein: 23
TG: 11
% weight of protein and TG in HDL
protein: 55
TG: 4
location of ApoA-1?
HDL
function of ApoA-1?
activates LCAT + structural role
location of ApoB-100?
VLDL, LDL
function of ApoB-100?
binds LDL receptor + structural role
location of ApoB-48?
chylomicron
function of ApoB-48?
structural role
location of ApoCII?
chylomicrons, VLDL, HDL
function of ApoCII?
activates lipoprotein lipase
location of ApoE?
chylomicron, VLDL, HDL
function of ApoE?
binds to LDL receptor - triggers clearance of VLDL and chylomicron remnants
what two apoproteins are encoded together on a single gene?
B-48: intestine (chylomicrons)
B-100: liver (VLDLs)
what is the mRNA difference b/w ApoB-48 and ApoB-100?
stop codon difference - C is changed to U in intestine mRNA (B-48)
chylomicron fate
once in blood, lipoprotein lipase (LPL) digests TG -> liver picks up remnants w/ apoE receptor
lipoprotein lipase
extracellular enzyme anchored to capillary walls of most tissues
what is LPL anchored by?
heparin sulfate
what is LPL activated by?
apoCII
adipose isoenzyme of LPL vs. muscle isoenzyme of LPL
adipose: higher Km, more active after meal when TGs high
muscle: lower Km, can obtain FAs even when low conc
what stimulates synthesis and secretion of the adipose isoenzyme of LPL?
insulin
de novo synthesis of FAs
primarily in the liver from 2C compounds - excess carb consumption, stored as TG in adipose tissue
is de novo synthesis of FAs the exact reverse of B-oxidation? why or why not?
no - completely different set of enzymes, occurs in cytosol, not mitochondria, and uses NADPH
what do both stages of de novo FA synthesis use?
acetyl-coA and multifunctional proteins in enzyme complexes
what multifunctional protein does stage 1 of de novo FA synthesis use?
acetyl-coA carboxylase
what multifunctional protein does stage 2 of de novo FA synthesis use?
FA synthetase
what are the ingredients for FA synthesis?
cytosolic acetyl-coA exported from mito as citrate and NADPH from PPP and malate -> pyruvate rxn
what does insulin/glucagon ratio induce synthesis of?
pyruvate DH, malic enzyme, citrate lyase
what does acetyl-coA carboxylase produce?
malonyl coA
what does malonyl coA inhibit and why?
CPT1 - when making malonyl coA, don’t want it transported into mitochondria for breakdown
what cofactor does acetyl-coA carboxylase require?
biotin
acetyl-coA carboxylase reaction
acetyl-coA + bicarb + ATP -> malonyl-coA + water + ADP + Pi
which is more active: polymer or monomer of acetyl-coA carboxylase?
polymer
how is acetyl-coA carboxylase regulated?
- citrate: polymerization and activation
- palmitoyl-coA: inhibition
- high calorie diet: induces transcription
- phosphorylation: inactivation
- insulin: activates (dephosphorylates)
function of FA synthase complex
sequentially adds 2C units from malonyl coA to the growing FA chain
FA synthase complex composition
1 protein: 7 different enzyme activities + acyl-carrier protein; dimer of identical polypeptides arranged head to tail
how many cycles of FA synthase occur before the final step of FA synthesis?
6
what is the final step of FA synthesis?
thioesterification to palmitate
what reactions occur in each cycle of FA synthase?
CRDRS:
- condensation
- reduction
- dehydration
- reduction
- scoot over (transacetylation)
what is located at each end of each FA synthase polypeptide?
SH - one derived from the vitamin pantothenic acid and one from a terminal Cys
what is the significance of the SH groups on FA synthase polypeptide?
can form thioesters with the acyl groups
what enzymes perform each reaction in one FA synthase cycle?
condensation = synthase reduction = reductase dehydration = dehydratase reduction = reductase scoot over = transacylase
which two reactions in the FA synthase cycle use NADPH?
the reductases
FA synthesis balanced equation
8 acetyl-coA + 7 ATP + 14 NADPH + 14 H+ –> palmitate + 8 coASH + 7 ADP + 7 Pi + 14 NADP+
difference b/w FA synthesis and FA oxidation
synthesis: requires ACP as acyl group carrier, NADPH as e- donor, and malonyl-coA as 2C donor
oxidation: uses coA as acyl carrier, FAD and NAD+ as e- acceptors, and acetyl-coA as 2C product
what stimulates FA synthase gene expression?
high insulin/glucagon ratio
what transcription factors are associated w/ FA synthase gene expression?
USFs (upstream stimulatory factors) and SREBPs (sterol response element binding proteins)
FA modifications
- elongation of long-chain FAs
- desaturation - addition of db’s
- formation of TAGs - storage form
- formation of phospholipids and sphingolipids
- formation of prostaglandins from linoleic acid
where does elongation of FAs occur?
in ER
what enzyms is responsible for elongation of FAs?
FA elongase
what is a common product of FA elongation from palmitate?
steric acid (18C)
what provides 2C units that are added onto palmitate?
malonyl-coA
what provides the reducing equivalents for FA elongation?
NADPH
what organ makes very long chain FAs (22-24 C) ?
brain
what is Stargardt-like macular degeneration?
juvenile eye disease caused by mutations in elongation of very long FAs - ELOVL4 gene
where does desaturation of FAs occur?
in ER
what is required for desaturation of FAs?
molecular oxygen
three enzyme steps for desaturation of FAs?
- NADH-cyt b5 reductase (flavoprotein w/ FAD)
- cytochrome b5 (uses Fe)
- desaturase (uses Fe coordinated to His)
what is the limit of human desaturases?
cannot add db’s past C-9
what are the most common human desaturated FAs?
palmitoleic acid - 16:1^9
oleic acid - 18:1^9
synthesis of TGs
glycerol or glucose -> glycerol-3-P -> phosphatidate -> diacylglycerol -> triacylglycerol -> transported in blood by VLDLs or stored in adipose tissue
where is glycerol kinase not found?
adipose tissue -> so glycerol in adipose is returned to liver
what is the primary site of lipid synthesis?
liver, but also can be done by adipose tissue
what stimulates synthesis and secretion of LPL?
insulin
how does phosphorylation affect hormone sensitive lipase?
activates it
what phosphorylates HPL?
protein kinase A
what regulates protein kinase A in the phosphorylation of HPL?
(+) increased cAMP
(+) low insulin/high glucagon
phospholipid synthesis
glycerol-3-P -> -> phosphatidate -> CDP-diacylglycerol -> phosphatidyl inositol (inositol - N head group)
second mechanism of phospholipid synthesis
head group (Ser) reacts w/ CTP to form CDP-serine then reacts with diacylglycerol
what is the key intermediate in phospholipid synthesis?
CDP-intermediate
respiratory distress syndrome
failure to produce enough phosphotidylcholine in lung surfactant
phospholipid degradation
cleaved by various phospholipases
what is special about the C2 fatty acid of phospholipids and what is done with it?
tends to be unsaturated (e.g. arachidonate) - cleaved in membrane by phospholipase A2 for prostaglandin synthesis
what are sphingolipids important for?
myelin sheath on nerve cells and antigenic determinants for the ABO blood groups
sphingolipid synthesis
serine + palmitoyl coA -> -> sphingosine -> (acylation of amino group) -> ceramide -> (add phosphatidyl choline, release diacylglycerol) -> sphingomyelin
what do gangliosides and cerebrosides add onto ceramide instead of choline?
sugar head groups
what generic pathway causes more problems for spingolipids and ceramides: synthesis or breakdown?
breakdown
