cholesterol and steroid metabolism.docx
TRANSCRIPT
-
7/23/2019 Cholesterol and Steroid Metabolism.docx
1/17
Cholesterol and Steroid Metabolism
I. Overview
Cholesterol characteristic steroid alcohol of
animal tissues
- Structural component of all cell
membranes (modulate its uidity)- Precursor of bile acids, steroid hormones,
and vitamin D (specialized tissues)
Liver regulate bodys cholesterol
homeostasis
Cholesterol sources:
Dietary cholesterol
!holesterol synthesized de novo by
e"trahepatic tissues and by the liver
itself
Fates of cholesterol:
#liminated from the liver asunmodi$ed cholesterol in the bile
!onverted to bile salts that are
secreted into the intestinal lumen
!omponent of plasma lipoproteins sent
to the peripheral tissues
Atherosclerosis lipid deposition leads to
pla%ue formation causing narro&ing of
blood vessels
II. Structure of Cholesterol
Cholesterol very hydrophobic
- !onsists of ' fused hydrocarbon rings
(steroid nucleus)- as an eight-carbon, branched
hydrocarbon chain attached to carbon *
of the D ring- +ing has at carbon .- +ing / has a double bond bet&een carbon
0 and carbon 1
A. Sterols- Steroids &ith 2 to 3 carbon atoms in
the side chain at carbon * and at
carbon .
Cholesterol ma4or sterol in animal tissues
Plant sterols (e.. !sitosterol" poorly
absorbed by humans
- fter entering enterocytes, they are
actively transported bac5 into the
intestinal lumen- +educe absorption of dietary cholesterol
used in dietary treatment of
hypercholesteremia
- !ommercially available trans fatty acid-
free margarine
#. Cholester$l esters- 6ot bound in membranes- 6ormally present in lo& levels in most
cells- 7ust be transported in association &ith
protein as a component of a lipoprotein
particle or be solubilized by phospholipids
and bile salts in the bile
III. S$nthesis of Cholesterol- #ndergonic- Driven by hydrolysis of the high-energy
thioester bond of acetyl coenzyme (!o)
and the terminal phosphate bond of 8P- +e%uires enzymes in both the cytosol and
the membrane of the smooth #+- +esponsive to changes in cholesterol
concentration
Cholesterol synthesized by virtually all
tissues in humans
Ma%e the larest contributions to the
bod$&s cholesterol 'ool: 9iver
:ntestine
drenal corte"
varies
8estes
Placenta
Acetate provides all the carbon atoms in
cholesterol
A)P* provides the reducing e%uivalents
:mbalance in regulation can lead to elevation
in circulating levels of plasma cholesterol &ith
the potential for vascular disease
A. S$nthesis of +!h$dro,$!+!
meth$llutar$l (*M-" CoA- ;irst < reactions are similar in the 5etone
bodies path&ay- +esult in the production of 7= !o
-
7/23/2019 Cholesterol and Steroid Metabolism.docx
2/17
;irst < acetyl !omolecules condenseto form acetoacetyl
!o
8hird molecule ofacetyl !o is addedproducing 7= !o
*M- CoA si"-carbon compound
Liver 'arench$mal cells
- contain < isozymes of HMG CoA
synthase- C$tosolic en$me:participates in
cholesterol synthesis- Mitochondrial en$me:functions in the
path&ay for 5etone body synthesis
#. S$nthesis of mevalonate- +eduction of 7= !o to mevalonate- !atalyzed by HMG CoA reductase- +ate-limiting and 5ey regulated step in
cholesterol synthesis- ccurs in the cytosol
- >ses < molecules of 6DP as reducingagent? releases !o
- :rreversible
HMG CoA reductase intrinsic membrane
protein of the #+ &ith the enzymes catalytic
domain pro4ecting into the cytosol
C. S$nthesis of cholesterol
IPP precursor of a family of molecules &ith
diverse functions, the isoprenoids
Cholesterol sterol isoprenoid
onsterol iso'renoids
e@g@ dolichol and ubi%uinone
Pren$lation covalent attachment of
farnesyl to proteins
- ne mechanism for anchoring proteins to
plasma membranes
S/ualene formed from 1 isoprenoid units
- . 8P are hydrolyzed per mevalonate
residue converted to :PP0otal:2 8P re%uired to ma5e the
polyisoprenoid s%ualene
Final ste' #+-associated path&ay
- :ncludes several diAerent enzymatic
reactions
Smith!Lemli!O'it s$ndrome (SLOS"
- +elatively common autosomal recessive
order of cholesterol biosynthesis- !aused by partial de$ciency in 7-
dehydrocholesterol-7-reductase- ne of several multisystem, embryonic
malformation syndromes associated &ith
impaired cholesterol synthesis
7-dehydrocholesterol-7-reductase
enzyme involved in the migration of the
double bond
-
7/23/2019 Cholesterol and Steroid Metabolism.docx
3/17
7evalonate is converted to 0-pyrophosphomevalonate in < stepseach of &hich transfers a phosphate
group from 8P
:sopentenyl pyrophosphate (:PP) isformed by the decarbo"ylation of 0-
pyrophosphomevalonate@ 8he reactionre%uires 8P@
:PP is isomerized to .,.-dimethylallylpyrophosphate (DPP)
:PP and DPP condense to form 3-carbon geranyl pyrophosphate (=PP)
Second molecule of :PP condenses&ith =PP to form 0-carbon farnesyl
pyrophosphate
< molecules of ;PP combine, releasingpyrophosphate, and are reducedforming the .3-carbon compound
s%ualene
S%ualene is converted to the sterollanosterol by a se%uence of reactionscatalyzed by #+-associated enzymes
that use
-
7/23/2019 Cholesterol and Steroid Metabolism.docx
4/17
:f sterols areabundant, they bindto S!P at its sterol-
sensing domain
/inding of S!P toother #+ membraneproteins (insigs) is
induced
+etention of S!P-S+#/P comple" in
the #+
Prevent theactivation of S+#/P
Do&n-regulation ofcholesterolsynthesis
:ntact sterol nucleus isconverted to bile acids and
bile salts
#"creted in the feces and bysecretion of cholesterol into
the bile
8ransported to the intestine foelimination
Some of the choleterol in theintestine is modi$ed by
bacteria before e"cretion
Primary compounds made areisomers coprostanol and
cholestanol - reducedderivatives of cholesterool
3. Sterol!accelerated en$me
deradationReductase a sterol-sensing integral
protein of the #+ membrane
5 sterol levels in the cell reductasebinds to insig proteins C ubi%uitination
and proteasomal degradation of the
reductase
+. Sterol!inde'endent
'hos'hor$lation6de'hos'hor$lationAMP-activated protein kinase (AMPK)
7phosphoprotein phosphatase
controls covalently the activity of CoA
reductasePhos'hor$lated inactive enzyme
)e'hos'hor$lated active enzymeAMPK activated by 7P 8P availability, cholesterol synthesis
8. *ormonal reulationE insulin and thyro"ine, upregulation of
e"pression of the gene for HMG CoA
reductaseE glucagon and glucocorticoids,
do&nregulation of e"pression of the gene
for HMG CoA reductase
9. Inhibition b$ drusStatin drus structural analogs of 7=
!o- re (or are metabolized to) reversible,
competitive inhibitors of HMG CoA
reductase- >sed to decrease plasma cholesterol
levels in patients &ith
hypercholesterolemia
I. )eradation of Cholesterol
Co'rostanol; cholestanol; andcholesterol ma5e up the bul5 of neutral
fecal sterols
. #ile Acids and #ile Salts
#ile &atery mi"ture of organic and inorganic
compounds
! Can either:
Pass directly from the liver &here it
is synthesized into the duodenum
through the common bile duct
-
7/23/2019 Cholesterol and Steroid Metabolism.docx
5/17
- groups are inserted atspeci$c positions on thesteroid structure
Double bond of cholesterol/ rings is reduced
ydrocarbon chain is
shortened by . carbons,introducing a carbo"ylgroup at the end of the
chain
ProductF GPrimaryG bileacidsF
cholic acid (triol)
and chenodeo"ycholic acid(diol)
Stored in the gallbladder &hen not
immediately needed for digestion
Phos'hatid$lcholine (lecithin" and bile
salts (con
-
7/23/2019 Cholesterol and Steroid Metabolism.docx
6/17
). Action of intestinal =ora on bile salts
#acteria in the intestine
- !an remove glycine and taurine from bile
salts C regenerating bile acids- !onvert some of the primary bile acids
into KsecondaryL bile acids by removing a
group, producingF
Deo"ycholic acid from cholic acid
9ithocholic acid from
chenodeo"ycholic acid
4. 4nterohe'atic circulation- /ile salts secreted into the intestine are
eMciently reabsorbed (N O0) and reused- 9iver converts both primary and
secondary bile acids into bile salts by
con4ugation &ith glycine or taurine C
secreted into the bile
Ileum via a a7!bile salt cotrans'orter
&here bile acids Q bile salts is primarily
absorbed
#ile acids 7 bile salts actively transported
out of the ileal mucosal cells into the portal
blood and are eMciently ta5en up by the
hepatocytes via an isoform of the
cotransporter
#ile acids hydrophobic
- +e%uire a carrier in the portal blood
Albumin carries bile acids in a noncovalent
comple"
4nterohe'atic circulation
- !ontinuous process of secretion of bile
salts into the bile C passage through the
duodenum &here some are converted to
bile acids C upta5e in the ileum C
subse%uent return to the liver as a mi"ture
of bile acids and salts
#ile acid se/uesterants (e..
cholest$ramine" bind bile acids in the gut
- Prevent reabsorption of bile acids C
promote e"cretion- >sed in the treatment of
hypercholesterolemia because the
removal of bile acids relieves the inhibition
on bile acid synthesis in the liver C divert
additional cholesterol into that path&ay
)ietar$ >ber also binds bile acids and
increases their e"cretion
F. #ile salt de>cienc$: cholelithiasis- disruption of the simultaneous movement
of cholesterol from the liver into the bile
and secretion of phospholipid and bile
salts C more cholesterol enters the bile
than can be solubilized by the bile salts
and phosphatidylcholine present C
precipitation of cholesterol in the
gallbladder C leading to cholesterol
gallstone disease- typically caused by bile acids in the bile
&hich may result fromF gross malabsorption of bile acids
from the intestine (seen in patients
&ith severe ileal disease)
obstruction of biliary tract C
interrupted enterohepatic
circulation
severe hepatic dysfunction C
decreased synthesis of bile salts or
other abnormalities in bile
production
e"cessive feedbac5 suppression of
bile acid synthesis R due to
accelerated rate of recycling of bile
acids- may also result from increased biliary
cholesterol e"cretion (seen &ith use of
$brates)
Fibrates (e.. em>broil" derivatives of
$bric acid
- used to reduce 8= levels in blood through
up-regulation of fatty acid -o"idation
La'arosco'ic cholec$stectom$ surgical
removal of gallbladder through a small
incision
- treatment of choice
Oral administration of chenodeo,$cholic
acid
- for patients &ho are unable to undergo
surgery
-
7/23/2019 Cholesterol and Steroid Metabolism.docx
7/17
- supplement bodys supply of bile acids C
gradual (months to years) dissolution of
gallstones
I. Plasma Li'o'roteins- Spherical macromolecular comple"es of
lipids and speci$c proteins
(apolipoproteins or apoproteins)
Li'o'rotein 'articles
! Include:
!hylomicrons (!7)
ery-lo&-density lipoproteins
9o&-density lipoproteins
igh-density lipoproteins
- DiAer in lipid and protein composition,
size, density and site of origin! Function both:
to 5eep their component lipids
soluble as they transport them in
the plasma
to provide an eMcient mechanism
for transporting their lipid contents
to (and from) the tissues- umans e"perience a gradual deposition
of lipid (especially cholesterol) in tissues C
potentially life-threatening occurrence
&hen the lipid deposition contributes to
pla%ue formation C atherosclerosis
A. Com'osition of 'lasma li'o'roteins
Li'o'roteins neutral lipid core (8= Q
cholesteryl esters) surrounded by a shell of
amphipathic apolipoproteins, phospholipid
and nonesteri$ed (free) cholesterol
- !onstantly interchange lipids and
apolipoproteins &ith each other
Shell of amphipathic apolipoproteins,
phospholipid, and nonesteri$ed cholesterol
(free)
- riented so that their polar portions are
e"posed on the surface of the lipoprotein,
thus ma5ing the particle soluble in
a%ueous solution
0A- and chlolesterol carried b$
li'o'roteins are obtained from:
Diet (e"ogenous source)
De novo synthesis (endogenous
source)
2. Sie and densit$ of li'o'rotein
'articlesCh$lomicrons lipoprotein particles
lo&est in density and largest in size- !ontain the highest percentage of
lipid- 9o&est percentage of protein
L)Ls and L)Ls
- Successively denser- igher ratios of protein to lipid
*)L 'articles
- Densest
Plasma li'o'roteins
- !an be separated on the basis of
their electrophoretic mobility or on thebasis of their density by
ultracentrifugation
3. A'oli'o'roteins- ssociated &ith lipoprotein particles
Functions:
Provide recognition sites for cell-
surface receptors
Serve as activators or coenzymes for
enzymes involved in lipoprotein
metabolism
- +e%uired as essential structuralcomponents of the particles and cannot be
removed (particles cannot be produced
&ithout them), &hereas others are
transferred freely bet&een lipoproteins
9 Ma
-
7/23/2019 Cholesterol and Steroid Metabolism.docx
8/17
!holesterol
;at-soluble vitamins
!holesteryl esters (plus additional
lipids made in these cells)
to the peripheral tissues
0A- account for close to O3 of lipids in a
chylomicron
2. S$nthesis of a'oli'o'roteins
A'oli'o'rotein #!8? uni%ue to
chylomicrons
- !onstitutes the 6-terminal, '2 of the
protein coded for by the gene for apo /
1ouh 41 &here synthesis of
apolipoprotein /-'2 begins C glycosylated as
it moves through the +#+ and =olgi
A'o #!2@@ synthesized by the liver
- ;ound in 9D9 and 9D9- +epresents the entire protein coded for by
the apo / gene
onsense codon created by
posttranscriptional editing of a cytosine to a
uracil in intestinal apo /-33 m+6
- llo& translation of only '2 of m+6
3. Assembl$ of ch$lomicrons- ccurs before transition from the #+ to the
=olgi, &here the particles are pac5aged in
secretory vesicles C fuse &ith the plasma
membrane releasing lipoproteins C enter
the lymphatic system C enter the blood
Smooth 41 &here enzymes involved in
8=, cholesterol, and phospholipid synthesis
are located
Microsomal 0A- transfer 'rotein
re%uired in assembly of apolipoproteins and
lipid into chylomicrons
- 9oads apo /-'2 &ith lipid
+. Modi>cation of nascent ch$lomicron
'articlesascent ch$lomicron particle released
by the intestinal mucosal cell- +eceives apolipoprotein # and ! &hen it
reaches the plasma
A'oli'o'rotein 4 recognized by hepatic
receptors
A'oli'o'rotein C includes apo !-::
necessary for activation of lipoprotein
lipase
ipoprotein lipase degrades the 8=
contained in the chylomicron
*)L source of these apolipoproteins
'@ )eradation of 0A- b$lipoprotein
lipase
ipoprotein lipase e"tracellular enzyme
that is anchored by heparin sulfate to the
capillary &alls of most tissues, but
predominantly those ofF
adipose tissue
cardiac muscle
s5eletal muscle
- activated by apo !-:: on circulating
lipoprotein particles- hydrolyzes 8= contained in lipoprotein
particles to yield fatty acids and glycerol
Adult liver does not have lipoprotein
lipase
Hepatic lipase found on the surface of
endothelial cells of the liver
- plays some role in 8= degradation in !7
and 9D9- particularly important in D9 metabolism
Fatt$ acids stored by the adipose or used
for energy by the muscle
- if not immediately ta5en up by a cell, 9!;
are transported by serum albumin until
their upta5e does occur
-l$cerol used by the liver inF
lipid synthesis
glycolysis
gluconeogenesis
ipoprotein lipasede>cienc$ or a'o C!II
(0$'e 2 h$'erli'o'roteinemia or familial
lipoprotein lipasede>cienc$"
- dramatic accumulation of chylomicron-8=in the plasma (hypertriacylglycerolemia)
even in the fasted state
0@ 1eulation oflipoprotein lipase
activit$
Insulin stimulate lipoprotein lipase
synthesis and transfer to the luminal surface
of the capillary (fed state)
-
7/23/2019 Cholesterol and Steroid Metabolism.docx
9/17
!hylomicron remnants bind tolipoprotein receptors
8a5en into the hepatocytes byendocytosis
#ndocytosed vesicle fuses&ith a lysosome
polipoproteins, cholesterylesters, and other components
of the remnant arehydrolytically degraded
mino acids, free cholesterol,and fatty acids are released
+eceptor is recycled
Adi'ose en$me has a lare m allo&s
removal of fatty acids from circulating
lipoprotein particles and their storage as 8=
only &hen plasma lipoprotein concentrations
are elevated
*eart muscle lipoprotein lipasehas a
small m
- llo&s the heart continuing access to the
circulating fuel, even &hen plasma
lipoprotein concentrations are lo&
Cardiac muscle has the highest
concentration of lipoprotein lipase reect
the use of fatty acids to provide much energy
needed for cardiac function
B. Formation of ch$lomicron remnants- s the chylomicron circulates and more
than O3 of 8= in its core is degraded by
lipoprotein lipase, the particle size
and E density- ! apoproteins but not apo # are returned
to D9
1emnant rapidly removed from the
circulation by the liver cell membranes
contain lipoprotein receptors that recognize
apo #
C. Metabolism of L)L
L)L produced in the liver
- !omposed predominantly of endogenous
8= (appro"imately 13)- Function:carry endogenous 8= from the
liver (site of synthesis) to the peripheral
tissues
Peri'heral tissues &here 8= is degraded
by lipoprotein lipase
Fatt$ liver (he'atic steatosis" occurs in
conditions in &hich there is an imbalance
bet&een hepatic 8= synthesis and the
secretion of 9D9
! Characteried b$:
besity
>ncontrolled diabetes mellitus
!hronic ethanol digestion
2. 1elease of L)L
-
7/23/2019 Cholesterol and Steroid Metabolism.docx
10/17
9D9 pass through thecirculation
8= is degraded bylipoprotein lipase
9D9 decrease in size andbecome denser
Surface components, includingthe ! and # apoproteins, are
returned to D9, but theparticles retain apo /-33
Some 8= are transferred from9D9 to D9 in an e"changereaction that concomitantlytransfers some cholesterylesters from D9 to 9D9
(accomplished by cholesterylester transfer protein or !#8P)
- 9D9 are secreted directly into the blood
by the liver as nascent 9D9 particles
containing apo /-33 must obtain apo !-
:: and apo # from circulating D9
Ch$lomicrons
- po !-:: is re%uired for activation of
lipoprotein lipase
Abetali'o'roteinemia rare
hypolipoproteinemia
- !aused by a defect in microsomal 8=
transfer protein (78P) C inability to load
apo / &ith lipid C no 9D9 or
chylomicrons are formed and 8=
accumulate in the liver and intestine
3. Modi>cation of circulatin L)L
-
7/23/2019 Cholesterol and Steroid Metabolism.docx
11/17
+. Production of L)L from L)L in the
'lasma- 9D9 is converted in the plasma to 9D9
Intermediate!densit$ li'o'roteins (I)L"
or L)L remnants observed during this
transition
I)L can also be ta5en up by cells through
receptor-mediated endocytosis that uses apo
# as the ligand
A'o 4 normally present in + isoforms:
4!3 binds poorly to receptors
#-.
#-'
Patients homozygotic for apo #-< are de$cient
in the clearance of chylomicron remnants and
:D9 have 0$'e III h$'erli'o'roteinemia
(familial d$sbetali'o'roteinemia orbroad beta disease" with
h$'ercholesterolemia and 'remature
atherosclerosis
- #-' isoform confers increased
susceptibility to and decreased age of
onset of late-onset lzheimer disease,
doubling lifetime ris5
). Metabolism of L)L
L)L contain much less 8= than their 9D9
predecessors- ave a high concentration of cholesterol
and cholesteryl esters
2. 1ece'tor!mediated endoc$tosis
Primar$ function of L)L 'articles:provide
cholesterol to the peripheral tissues (or return
it to the liver) by binding to cell surface
membrane 9D9 receptors that recognize apo
/-33 (but not apo /-'2) these receptors
can also bind apo #? they are also 5no&n as
apo /-33Tapo # receptors
-
7/23/2019 Cholesterol and Steroid Metabolism.docx
12/17
9D9 receptors are negatively chargedglycoproteins that are clustered in pits oncell membranes@ 8he cytosolic side of the
pit is coated &ith the protein clathrin,&hich stabilizes the shape of the pit
fter binding, the 9D9-receptor comple" isinternalized by endocytosis
8he vesicle containing 9D9 loses itsclathrin coat and fuses &ith other similar
vesicles, forming larger vesicles(endosomes)
8e p of the endosome falls due to theproton-pumping activity of endosomal
A!Pase- allo&s separation of 9D9 fromits receptor
+eceptor migrate to one side of theendosome, &hereas the 9D9s stay free
&ithin the lumen of the vesicle
8he receptors can be recycled, &hereasthe lipoprotein remnants in the vesicle aretransferred to lysosomes and degraded bylysoso"al acid hydrolases, releasing
free cholesterol, amino acids, fatty acids,and phospholipids@ 8hese compounds are
reutralized by the cell@
0$'e II h$'erli'idemia (familial
h$'ercholesterolemia; F*" and 'remature
atherosclerosis
- de$ciency of functional 9D9 receptors- E plasma 9D9 and plasma cholesterol
F* can also be caused byF
Eproteaseactivity that degrades the
receptor
Defects in apo /-33 that reduce its
binding to the receptor
C1L compartment for uncoupling of receptor
and ligand
- Bhere receptors migrate to
Dolman disease
- Storage disease caused by rare autosomal
recessive de$ciencies in the ability tohydrolyze lysosomal cholesteryl esters
iemann!Pic% disease; 0$'e C
- :nability to transport unesteri$ed
cholesterol out of the lysosome
3. 4Eect of endoc$tosed cholesterol on
cellular cholesterol homeostasisa@ HMG CoA reductaseis inhibited by E
cholesterol? de novo cholesterol synthesis
b@ synthesis of ne& 9D9 receptor protein
by e"pression of 9D9 receptor gene C
limited entry of 9D9 cholesterol into cellsc# :f the cholesterol is not re%uired
immediately for some structural or
synthetic purpose, it is esteri$ed by acyl
CoA$ cholesterol acyltrans%erase
(ACA!)
S14 and S14#P (S14#P!3" involved in the
regulation of 9D9 receptor gene
ACA! transfers fatty acid from fatty acyl
!o derivative to cholesterol? Product:
cholesteryl ester that can be stored in the cell
- ctivity is enhanced in the presence of
increased intracellular cholesterol
+. 'ta%e of chemicall$ modi>ed L)L b$
macro'hae scavener
Macro'haes possess high levels of
scavenger receptor activity
-
7/23/2019 Cholesterol and Steroid Metabolism.docx
13/17
Scavener rece'tor class A (S1!A"
- !an bind a broad range of ligands- 7ediate endocytosis of chemically
modi$ed 9D9 in &hich the lipid
components of apo / have been o"idized- 6ot do&n-regulated in response to E
intracellular cholesterol
Cholester$l esters accumulate in
macrophages
- !ause transformation of macrophages into
KfoamL cells participate in the formation
of atherosclerotic pla%ue
4. Metabolism of *)L
*)L comprise of heterogeneous family of
lipoproteins &ith a comple" metabolism
*)L 'articles formed in blood by the
addition of lipidto apo -
A'o A!2 apolipoprotein made by the liver
and intestine and secreted into blood
- ccounts for about *3 of the apoproteins
in D9
Functions of *)L
2. *)L is a reservoir of a'oli'o'roteins
*)L 'articles serve as circulating reservoir
of apo !-::
A'o C!II apolipoprotein that is transferred
to 9D9 and chylomicrons
- ctivator of lipoprotein lipase
A'o 4 apolipoprotein re%uired for the
receptor-mediated endocytosis of :D9s and
chylomicron remnants
3. *)L u'ta%e of unesteri>ed
cholesterol
ascent *)L dis5-shaped particles
containing primarily phospholipid (largely
phosphatidylcholine) and apolipoproteins , !,
and #- 8a5e up cholesterol from non-hepatic
(peripheral) tissues and return it to the
liver as cholesteryl esters
*)L 'articles e"cellent acceptors of
unesteri$ed cholesterol as a result of their
high concentration of phospholipids, &hich
are important solubilizers of cholesterol
+. 4steri>cation of cholesterol
Cholesterol &hen ta5en up by D9, it is
immediately esteri$ed by the plasma enzyme
lecithin$cholesterol acyltrans%erase
(CA! or PCA!? P U Phosphatidylcholine)
CA! synthesized by the liver
- /inds to nascent D9- Activated b$:po -:- 8ransfers fatty acid from carbon < of
phosphatidylcholine to cholesterolProduct:hydrophobic cholesteryl ester
(se%uestered in the core of D9) and
lysophosphatidylcholine (binds to albumin)
4steri>cation maintains cholesterol
concentration gradient allo& continued
eVu" of cholesterol to D9
)iscoidal nascent *)L accumulatescholesteryl esters
- ;irst becomes a spherical, relatively
cholesteryl ester-poor D9. C cholesteryl
ester-rich D9< particle that carries these
esters to the liver
Cholesterol ester transfer 'rotein (C40P"
moves some of the cholesteryl esters from
D9 to 9D9 in e"change for 8= C relieve
product inhibition of CA!
/ecause 9D9 are catabolized to 9D9,
cholesteryl esters are ultimately ta5en up by
the liver
8. 1everse cholesterol trans'ort! Involves
eVu" of cholesterol from
peripheral cells to D9 mediated,
at least in part, by the transport
protein /!
esteri$cation of cholesterol by
CA! binding of cholesteryl ester-rich
D9 (D9
-
7/23/2019 Cholesterol and Steroid Metabolism.docx
14/17
- Selective transfer of cholesterol from
peripheral cells to D9 and from D9 to
the liver for bile acid synthesis or disposal
via the bile and to steroidogenic cells for
hormone synthesis! #asis for
inverse relationship seen bet&een
plasma D9 concentration and
atherosclerosis
D9s designation as the KgoodL
cholesterol carrier
0anier disease very rare de$ciency of
/!
- !haracterized by virtual absence of D9
particles due to degradation of lipid-poor
apo -
S1!#2 (scavener rece'tor class # t$'e
2"
- !ell-surface receptor- - mediates the upta5e of cholesteryl esters
by the liver- /inds D9
Hepatic lipase can degrade both 8= and
phospholipids
- Participates in the conversion of D9< to
D9.
A#CA2 an 8P-binding cassette (/!)
protein
A#C 'roteins use energy from 8P
hydrolysis to transport materials, including
lipids, in and out of cells and across
intracellular compartments
)efects in s'eci>c A#C 'roteins result
in:
W-lin5ed adrenoleu5odystrophy
+espiratory distress syndrome due todecreased surfactant secretion
!ystic $brosis
F. 1ole of li'o'rotein (a" in heart
disease
Li'o'rotein (a" or L' (a"
- Particle, &hen present in large %uantities
in the plasma, is associated &ith an
increased ris5 of coronary heart disease
- 6early identical in structure to an 9D9
particle- Distinguishing featureF presence of
additional apolipoprotein molecule (apo
(a)) that is covalently lin5ed at a single
site to apo /-33
!irculating levels of 9p(a) are determined
primarily by genetics
)iet may play some role as trans fatty acids
have been sho&n to E 9p(a)
4stroen- both 9D9 and 9p(a)
A'o(a" structurally homologous to
plasminogen
Plasminoen precursor of bloodprotease
&hose target is $brinFibrin main protein component of blood
clots
9p(a) slo&s do&n the brea5do&n of blood
clots that trigger heart attac5s because it
competes &ith plasminogen for binding to
$brin
iacin reduces 9p(a) and raises D9
II. Steroid *ormones
Cholesterol precursor of all classes of
steroid hormones:
=lucocorticoids e@g@ cortisol
7ineralocorticoids e@g@ aldosterone
Se" hormones e@g@ androgens,
estrogens, and progestins
Corticosteroids collective term for
glucocorticoids and mineralocorticoids
Adrenal corte, &here synthesis and
secretion of cortisol, aldosterone, and
androgens occur
Ovaries and 'lacenta &here synthesis andsecretion of estrogens and progestins occur
0estes &here synthesis and secretion of
testosterone occurs
Steroid hormones transported by the
blood from their sites of synthesis to their
target organs
- 7ust be comple"ed &ith a plasma protein
because of their hydrophobicity
-
7/23/2019 Cholesterol and Steroid Metabolism.docx
15/17
Plasma albumin can act as a nonspeci$c
carrier
- carry aldosterone
S'eci>c steroid!carrier 'lasma 'roteins
- bind steroid hormones more tightly than
does albumin
#@g@ corticosteroid-binding globulin
(transcortin)
- responsible for transporting cortisol
A. S$nthesis of steroid hormones- :nvolves shortening hydrocarbon chain of
cholesterol and hydro"ylation of the
steroid nucleus
Initial and rate!limitin reaction
converts cholesterol to the
-
7/23/2019 Cholesterol and Steroid Metabolism.docx
16/17
- Primar$ eEect on %idne$ tubules:
stimulates sodium upta5e and potassium
e"cretion- E /P
Outer la$er (ona lomerulosa" of the
adrenal corte, &here aldosterone is
produced induced by plasma 6aQTHQratio
and by angiotensin ::
Aniotensin II an octapeptide
- Produced from angiotensin : (decapeptide)
by angiotensin-converting enzyme (!#)
found predominantly in the lungs, but
&hich is also distributed &idely in the
body- /inds to cell-surface receptors- #Aects are mediated through the
phosphatidylinositol ',0-bisphosphate
(P:P
-
7/23/2019 Cholesterol and Steroid Metabolism.docx
17/17
#ach steroid hormonediAuses across the plasmamembrane of its target cell
and binds to a speci$ccytosolic or nuclear receptor
+eceptor-ligand comple"esaccumulate in the nucleus
+eceptor-ligand comple"esdimerize
/ind to speci$c regulatoryD6 se%uences (hromone-response elements, +#) inassociation &ith coactivator
proteins
Promoter activation andincreased transcription of
targeted genes
1ece'tors for steroid hormones; th$roid
hormone; retinoic acid; and 2;39!
dih$dro,$cholecalciferol (vitamin )"
members of a KsuperfamilyL of structurally
related gene regulators that function in a
similar &ay
4. Further metabolism of steroid
hormones
Steroid hormones generally converted
into inactive metabolic e"cretion products in
the liver
1eactions include:
+eduction of unsaturated bonds
:ntroduction of additional hydro"yl
groups
1esultin structure:made more soluble bycon4ugation &ith glucuronic acid or sulfate
(from .-phosphoadenosyl-
0phosphosulfate)
ppro"imately