Cholesterol and Steroid Metabolism
Cholesterol and Steroid Metabolism
I.
Overview
Cholesterol characteristic steroid alcohol of animal
tissues
Structural component of all cell membranes
(modulate its fluidity)
Precursor of bile acids, steroid hormones, and
vitamin D (specialized tissues)
Liver regulate bodys cholesterol homeostasis
Cholesterol sources:
Dietary cholesterol
Cholesterol synthesized de novo by
extrahepatic tissues and by the liver itself
Fates of cholesterol:
Eliminated from the liver as unmodified
cholesterol in the bile
Converted to bile salts that are secreted into
the intestinal lumen
Component of plasma lipoproteins sent to the
peripheral tissues
Atherosclerosis lipid deposition leads to plaque
formation causing narrowing of blood vessels
II.
Structure of Cholesterol
Cholesterol very hydrophobic
Consists of 4 fused hydrocarbon rings (steroid
nucleus)
Has an eight-carbon, branched hydrocarbon chain
attached to carbon 17 of the D ring
Ring A has OH at carbon 3
Ring B has a double bond between carbon 5 and
carbon 6
A.
-
Sterols
Steroids with 8 to 10 carbon atoms in the side
chain at carbon 17 and OH at carbon 3
Cholesterol major sterol in animal tissues
Plant sterols (e.g. -sitosterol) poorly absorbed by
humans
After entering enterocytes, they are actively
transported back into the intestinal lumen
Reduce absorption of dietary cholesterol used in
dietary treatment of hypercholesteremia
Commercially available trans fatty acid-free
margarine
B.
-
Cholesteryl esters
Not bound in membranes
Normally present in low levels in most cells
Must be transported in association with protein as
a component of a lipoprotein particle or be
solubilized by phospholipids and bile salts in the
bile
III.
Synthesis of Cholesterol
Endergonic
Driven by hydrolysis of the high-energy thioester
bond of acetyl coenzyme A (CoA) and the terminal
phosphate bond of ATP
Requires enzymes in both the cytosol and the
membrane of the smooth ER
Responsive to changes in cholesterol
concentration
Cholesterol synthesized by virtually all tissues in
humans
Make the largest contributions to the bodys
cholesterol pool:
Liver
Intestine
Adrenal cortex
Ovaries
Testes
Placenta
Acetate provides all the carbon atoms in cholesterol
NADPH provides the reducing equivalents
Imbalance in regulation can lead to elevation in
circulating levels of plasma cholesterol with the
potential for vascular disease
A.
-
Synthesis of mevalonate
Reduction of HMG CoA to mevalonate
Catalyzed by HMG CoA reductase
Rate-limiting and key regulated step in cholesterol
synthesis
Occurs in the cytosol
Uses 2 molecules of NADPH as reducing agent;
releases CoA
Irreversible
HMG CoA reductase intrinsic membrane protein of
the ER with the enzymes catalytic domain projecting
into the cytosol
C. Synthesis of cholesterol
IPP precursor of a family of molecules with diverse
functions, the isoprenoids
Cholesterol sterol isoprenoid
Nonsterol isoprenoids
e.g. dolichol and ubiquinone
Prenylation covalent attachment of farnesyl to
proteins
One mechanism for anchoring proteins to plasma
membranes
Squalene formed from 6 isoprenoid units
3 ATP are hydrolyzed per mevalonate residue
converted to IPP
Total: 18 ATP required to make the
polyisoprenoid squalene
Down-regulation of
cholesterol synthesis
2. Sterol-accelerated enzyme degradation
Reductase a sterol-sensing integral protein of
the ER membrane
sterol levels in the cell reductase binds to insig
proteins ubiquitination and proteasomal
degradation of the reductase
3. Sterol-independent
phosphorylation/dephosphorylation
AMP-activated protein kinase (AMPK) +
phosphoprotein phosphatase controls covalently
the activity of CoA reductase
Phosphorylated inactive enzyme
Dephosphorylated active enzyme
AMPK activated by AMP
ATP availability, cholesterol synthesis
4. Hormonal regulation
insulin and thyroxine, upregulation of expression
of the gene for HMG CoA reductase
glucagon and glucocorticoids, downregulation of
expression of the gene for HMG CoA reductase
5. Inhibition by drugs
Statin drugs structural analogs of HMG CoA
Are (or are metabolized to) reversible, competitive
inhibitors of HMG CoA reductase
Used to decrease plasma cholesterol levels in
patients with hypercholesterolemia
IV.
Degradation of Cholesterol
Intact sterol nucleus is converted to
bile acids and bile salts
Enterohepatic circulation
Bile salts secreted into the intestine are efficiently
reabsorbed (> 95%) and reused
Liver converts both primary and secondary bile
acids into bile salts by conjugation with glycine or
taurine secreted into the bile
B. Metabolism of chylomicrons
Intestinal mucosal cells where chylomicrons are
assembled
Chylomicrons carry:
Dietary TAG
Cholesterol
Fat-soluble vitamins
Cholesteryl esters (plus additional lipids made
in these cells)
to the peripheral tissues
TAG account for close to 90% of lipids in a
chylomicron
1. Synthesis of apolipoproteins
Apolipoprotein B-48 unique to chylomicrons
Constitutes the N-terminal, 48% of the protein
coded for by the gene for apo B
Rough ER where synthesis of apolipoprotein B-48
begins glycosylated as it moves through the RER
and Golgi
Apo B-100 synthesized by the liver
Found in VLDL and LDL
Represents the entire protein coded for by the apo
B gene
Nonsense codon created by posttranscriptional
editing of a cytosine to a uracil in intestinal apo B-100
mRNA
Allow translation of only 48% of mRNA
2. Assembly of chylomicrons
Occurs before transition from the ER to the Golgi,
where the particles are packaged in secretory
vesicles fuse with the plasma membrane
releasing lipoproteins enter the lymphatic
system enter the blood
Smooth ER where enzymes involved in TAG,
cholesterol, and phospholipid synthesis are located
Microsomal TAG transfer protein required in
assembly of apolipoproteins and lipid into chylomicrons
Loads apo B-48 with lipid
3. Modification of nascent chylomicron particles
Nascent chylomicron particle released by the
intestinal mucosal cell
Receives apolipoprotein E and C when it reaches
the plasma
Apolipoprotein E recognized by hepatic receptors
Apolipoprotein C includes apo C-II necessary for
activation of lipoprotein lipase
Receptor is recycled
C. Metabolism of VLDL
VLDL produced in the liver
Composed predominantly of endogenous TAG
(approximately 60%)
Function: carry endogenous TAG from the liver (site
of synthesis) to the peripheral tissues
Wolman disease
Storage disease caused by rare autosomal
recessive deficiencies in the ability to hydrolyze
lysosomal cholesteryl esters
Niemann-Pick disease, Type C
Inability to transport unesterified cholesterol out of
the lysosome
THe pH of the endosome falls due to the protonpumping activity of endosomal ATPase - allows
separation of LDL from its receptor
Angiotensin II an octapeptide
Produced from angiotensin I (decapeptide) by
angiotensin-converting enzyme (ACE) found
predominantly in the lungs, but which is also
distributed widely in the body
Binds to cell-surface receptors
Effects are mediated through the
phosphatidylinositol 4,5-bisphosphate (PIP2)
pathway and not by cAMP
Inhibitors of ACE are used to treat renin-dependent
hypertension
Angiotensin I produced in the blood by cleavage of an
inactive precursor (angiotensin) secreted by the liver
Cleavage is accomplished by the enzyme renin,
made and secreted by the kidney
3. Androgens
Inner (zona reticularis) and middle layers of the adrenal
cortex produce androgens, primarily
dehydroepiandrosterone and androstenedione
Adrenal androgens weak
Converted in peripheral tissues to testosterone
and to estrogens
Testosterone stronger androgen
Estrogens derived from androstenedione and
testosterone by aromatase (CYP19)
Aromatase inhibitors used in the treatment of
estrogen-responsive breast cancer in post-menopausal
women
C. Secretion of steroid hormones from gonads
Testes and ovaries synthesize hormones necessary
for sexual differentiation and reproduction
Gonadotropin-releasing hormone single
hypothalamic-releasing factor
Stimulates the anterior pituitary to release the:
Glycoproteins
Luteinizing hormone (LH) stimulates the
testes to produce testosterone and the
ovaries to produce estrogens and
progesterone
Follicle-stimulating hormone (FSH)
regulates the growth of ovarian follicles
and stimulates testicular spermatogenesis
LH and FSH bind to surface receptors
Cause an increase in cAMP
Receptor-ligand complexes
accumulate in the nucleus
Receptor-ligand complexes
dimerize