cholesterol and steroid metabolism.docx

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


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


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


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


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


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


7/17

- 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


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)


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


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


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


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


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


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


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


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


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

cholesterol and steroid metabolism.docx

Documents