BIOC 460 DR. TISCHLER
LECTURE 29
CHOLESTEROL & STEROIDS
OBJECTIVES: 1. For cholesterol: a) list its physiological
functions b) describe its synthesis c) list 6 groups of hormones
produced from it and their function 2. For bile acids (salts): a)
list their physiological functions b) describe their synthesis 3.
For the steroid hormones: a) identify the five general classes b)
for synthesis of cortisol and aldosterone: identify the tissue
where this occurs; outline the general pathways c) outline the
pathway for synthesis of androgens in the adrenal cortex and in the
testes, and for estrogen in the ovaries and adipose tissue. 4. Name
disorders associated with vitamin D deficiency 5. Name disorder
associated with estrogen loss
CHOLESTEROL FACTSsynthesized from acetyl CoA and eliminated as
bile acids precursor of all other steroids in the body product of
animal metabolism - in foods of animal origin amphipathic lipid
(hydrophobic and hydrophilic portions) storage form is cholesterol
ester found in most tissues.
hydrophilic
O || R-C-O Cholesterol ester (1st ring only) R = fatty acid
hydrocarbon chain
HO
CHOLESTEROL FACTS
essential structural component of membranes transported in the
circulation in lipoproteins
ROLES OF CHOLESTEROL AND BILE ACIDS (SALTS)
The physiological roles of cholesterol include: a) an important
lipid component of biological membranes, b) precursor of steroid
hormones and c) source of bile acids. Bile acids are polar
derivatives of cholesterol and aid in: a) lipid digestion b) lipid
absorption c) cholesterol excretion
Cholesterol
CYTOPLASM CO2
MITOCHONDRIAL MATRIX
Pyruvate NADPH Hydroxymethyl ME glutaryl CoA NADP+ Malate
CoAAcCoA
PyruvateATP, CO2 PC ADP, Pi Oxaloacetate CS Acetyl CoA
HMG-S
NAD+ MDH NADH
Acetoacetyl CoA CoA thiolase2 Acetyl CoA
Oxaloacetate ADP+Pi ATP, CoA Citrate Citrate
CL
Figure 1. Formation of hydroxymethylglutaryl CoA for the
synthesis of cholesterol.
KEY CYTOPLASMIC REACTIONS ASSOCIATED WITH CHOLESTEROL
SYNTHESIS
citrate lyase: citrate + ATP + CoA p oxaloacetate + acetyl CoA +
ADP + Pi thiolase: 2 acetyl CoA p acetoacetyl CoA + CoA HMG CoA
synthase: acetoacetyl CoA + acetyl CoA p hydroxymethylglutaryl CoA
(HMG CoA) + CoA
Stage 1 Acetyl CoA (C2) HMG-CoA NADPH HMG-CoA Reductase NADP+
Mevalonate (C6) Stage 2 Mevalonate3ATP 3ADP
rate-determining step cholesterol is feedback inhibitor
mevalonate is feedback inhibitor target site for statin drugs Stage
3 Squalene (C30) Stage 4 Lanosterol (C30) O2 NADPH NADP+ 3 CH3(19
steps)
Cyclization O2 CO2 Squalene Active Isoprenoids (C5) NADPH
epoxidase/ Several + NADPH cyclase Condensation Steps NADP NADP+
Lanosterol (C30) Squalene (C30) (4-ring structure)
Cholesterol (C27)
Figure 2. The four stages of cholesterol biosynthesis
7E-hydroxylaseCholesterol + NADPH + O2 7-hydroxycholesterol +
NADP+
Figure 3. The initial reaction, 7E-hydroxylase, in the
conversion of cholesterol to bile acids. Rate-determining step
Repressed (decreased synthesis) by bile salts Induced (increased
synthesis) by cholesterol
Table 1. Functions of Hormones Derived from CholesterolProduct
Progesterone Glucocorticoids (cortisol) (produced in adrenal
cortex) (catabolic steroid) Mineralocorticoids (aldosterone)
(produced in adrenal glands) Functions prepares uterus lining for
implantation of ovum promote gluconeogenesis; favor breakdown of
fat and protein (fuel mobilization); anti-inflammatory maintains
blood volume and blood pressure by increasing sodium reabsorption
by kidney
Table 1. Functions of Hormones Derived from CholesterolProduct
Androgens (strongest = testosterone) (produced in testes primarily
but weak androgens in adrenal cortex) (anabolic steroid) Functions
development of male secondary sex characteristics; prevents bone
resorption
Estrogen development of female (produced in ovaries primarily
but also secondary sex in adipose cells of males and females)
characteristics; prevents bone resorption Vitamin D (not a steroid
hormone) (produced in the skin in response to UV light and
processed to active form in kidney) intestinal calcium absorption;
promotes bone formation; prevents phosphate loss by kidneys
activated to turn on pathways Cholesterol Pregnenolone
Progesterone
Progesterone 21-hydroxylase
11-Deoxycortisone
Aldosterone
Progesterone 21-hydroxylase
11-Deoxycortisol
Cortisol
Figure 4. General pathways for the synthesis of aldosterone and
cortisol in the adrenal cortex
Pregnenolone
DHEA
Androstenedione Andro
Figure 5. Pathway for formation of androgens in the adrenal
cortex. Beware of the hype about taking DHEA Cortisol made in same
cells as androstenedione
Cholesterol Progesterone
Pregnenolone Androstenedione
Progesterone Testosterone (pathway ends here in testes)
Estrone (produced in both male and female adipose cells)
Estradiol (pathway continues to here in ovaries)
In obese men, overproduction of estrogen in fat cells can cause
gynecomastia = excessive male breast development
Figure 6. Pathways for the synthesis of testosterone (testes)
and the estrogens estradiol (ovaries) and estrone (adipose
cells)
Liver Diet 25OHase HO Vitamin D3 UV from sunlight Skin HO 25(OH)
D3 Kidney 1-OHase
OH
OHase = hydroxylase
Specific receptors in intestine, bone, kidney Ca: Intestinal
absorption Renal reabsorption PO4: Intestinal absorption Renal
reabsorption
OH
HO
7 HO OH
Provitamin D3 (7-dehydrocholesterol: Intermediate in cholesterol
synthesis)
1,25(OH)2 D3(active hormone form)
Figure 7. Photobiosynthesis of vitamin D3 and its metabolism
