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.pdfThe primary stimulus for aldosterone production is the octapeptide angiotensin II, although
hyperkalemia (greater than normal levels of potassium in the blood) or hyponatremia (less than normal
levels of sodium in the blood) may stimulate aldosterone synthesis directly as well. ACTH has a
permissive action in aldosterone production. It allows cells to respond optimally to their primary
stimulus, angiotensin II.
Although aldosterone is the major mineralocorticoid in humans, excessive production of a
weaker mineralocorticoid, DOC, which occurs in patients with a deficiency of the 11hydroxylase (the P450C11 enzyme, CYP11B1), may lead to clinical signs and symptoms of
mineralocorticoid excess even though aldosterone secretion is suppressed in these patients.
D. Synthesis of the Adrenal Androgens
Adrenal androgen biosynthesis proceeds from cleavage of the two-carbon side chain of 17-
hydroxypregnenolone at C17 to form the 19-carbon adrenal androgen DHEA and its sulfate derivative
(DHEAS) in the zona reticularis of the adrenal cortex (see Fig. 32.21). These compounds, which are
weak androgens, represent a significant percentage of the total steroid production by the normal adrenal
cortex and are the major androgens synthesized in the adrenal gland. Androstenedione, another weak adrenal androgen, is produced by oxidation of the β-hydroxy group to
a carbonyl group by 3β-hydroxysteroid dehydrogenase. This androgen is converted to testosterone
primarily in extraadrenal tissues. Although the adrenal cortex makes very little estrogen, the weak adrenal
androgens may be converted to estrogens in the peripheral tissues, particularly in adipose tissue (Fig.
32.23).E. Synthesis of Testosterone
Luteinizing hormone (LH) from the anterior pituitary stimulates the synthesis of testosterone and other
androgens by the Leydig cells of the human testicle. In many ways, the pathways leading to androgen
synthesis in the testicle are similar to those described for the adrenal cortex. In the human testicle, the
predominant pathway leading to testosterone synthesis is through pregnenolone to 17α-
hydroxypregnenolone to DHEA (the Δ5 pathway), and then from DHEA to androstenedione, and from
androstenedione to testosterone (see Fig. 32.21). As for all steroids, the rate-limiting step in testosterone
production is the conversion of cholesterol to pregnenolone. LH controls the rate of side-chain cleavage
from cholesterol at carbon 21 to form pregnenolone and thus regulates the rate of testosterone synthesis. In
its target cells, the double bond in ring A of testosterone is reduced through the action of 5α-reductase,
forming the active hormone dihydrotestosterone (DHT).
Congenital adrenal hyperplasia (CAH) is a group of diseases caused by a genetically determined deficiency in a variety of enzymes required for cortisol synthesis. The most
common deficiency is that of 21α-hydroxylase (CYP21), the activity of which is necessary to
convert progesterone to 11-DOC and 17α-hydroxyprogesterone to 11-deoxycortisol. Thus, this
deficiency reduces both aldosterone and cortisol production without affecting androgen
production. If the enzyme deficiency is severe, the precursors for aldosterone and cortisol
production are shunted to androgen synthesis, producing an overabundance of androgens, which
leads to prenatal masculinization in females and postnatal virilization of males. Another enzyme
deficiency in this group of diseases is that of 11β-hydroxylase (CYP11B1), which results in the
accumulation of 11-DOC. An excess of this mineralocorticoid leads to hypertension (through
binding of 11-DOC to the aldosterone receptor). In this form of CAH, 11-deoxycortisol also
accumulates, but its biologic activity is minimal, and no specific clinical signs and symptoms
result. The androgen pathway is unaffected, and the increased ACTH levels may increase the
levels of adrenal androgens in the blood. A third possible enzyme deficiency is that of 17α-
hydroxylase (CYP17). A defect in 17α-hydroxylase leads to aldosterone excess and hypertension;
however, because adrenal androgen synthesis requires this enzyme, no virilization occurs in these
patients.F. Synthesis of Estrogens and Progesterone
Ovarian production of estrogens, progestogens (compounds related to progesterone), and androgens
requires the activity of the cytochrome P450 family of oxidative enzymes used for the synthesis of other
steroid hormones. Ovarian estrogens are C18 steroids with a phenolic hydroxyl group at C3 and either a
hydroxyl group (estradiol) or a ketone group (estrone) at C17. Although the major steroid-producing
compartments of the ovary (the granulosa cell, the theca cell, the stromal cell, and the cells of the corpus
luteum) have all of the enzyme systems required for the synthesis of multiple steroids, the granulosa cells
secrete primarily estrogens, the thecal and stromal cells secrete primarily androgens, and the cells of the
corpus luteum secrete primarily progesterone.
Biologically, the most potent circulating androgen is testosterone. Approximately 50% of
the testosterone in the blood in a normal woman is produced equally in the ovaries and in
the adrenal cortices. The remaining half is derived from ovarian and adrenal androstenedione,
which, after secretion into the blood, is converted to testosterone in adipose tissue, muscle, liver,
and skin. The adrenal cortex, however, is the major source of the relatively weak androgen
DHEA. The serum concentration of its stable metabolite, DHEAS, is used as a measure of adrenal
androgen production in hyperandrogenic patients with diffuse excessive growth of secondary
sexual hair (e.g., facial hair as well as that in the axillae, the suprapubic area, the chest, and the
upper extremities).
The ovarian granulosa cell, in response to stimulation by follicle-stimulating hormone (FSH) from the
anterior pituitary gland and through the catalytic activity of P450 aromatase (CYP19), converts
testosterone to estradiol, the predominant and most potent of the ovarian estrogens (see Fig. 32.21).
Similarly, androstenedione is converted to estrone in the ovary, although the major site of estrone
production from androstenedione occurs in extraovarian tissues, principally skeletal muscle and adipose
tissue.
G. Vitamin D Synthesis
Vitamin D is unique in that it can be either obtained from the diet (as vitamin D2 or D3) or synthesized
from a cholesterol precursor, a process that requires reactions in the skin, liver, and kidney. The
calciferols, including several forms of vitamin D, are a family of steroids that affect calcium homeostasis
(Fig. 32.24). Cholecalciferol (vitamin D3) requires ultraviolet light for its production from 7-
dehydrocholesterol, which is present in cutaneous tissues (skin) in animals and available from ergosterol
in plants. This irradiation cleaves the carbon–carbon bond at C9–C10, opening the B-ring to form
cholecalciferol, an inactive precursor of 1,25-(OH)2-cholecalciferol (calcitriol). Calcitriol is the most
potent biologically active form of vitamin D (see Fig. 32.24).The results of the blood tests on Vera L. showed that her level of testosterone was normal
but that her serum DHEAS level was significantly elevated. Which tissue was the most likely source of the androgens that caused Vera’s hirsutism (a male pattern of secondary sexual
hair growth)?
Vera L.’s hirsutism was most likely the result of a problem in her adrenal cortex that caused
excessive production of DHEA.
The formation of calcitriol from cholecalciferol begins in the liver and ends in the kidney, where the
pathway is regulated. In this activation process, carbon 25 of vitamin D2 or D3 is hydroxylated in the
microsomes of the liver to form 25-hydroxycholecalciferol (calcidiol). Calcidiol circulates to the kidneybound to vitamin D–binding globulin (transcalciferin). In the proximal convoluted tubule of the kidney, a
mixed-function oxidase, which requires molecular O2 and NADPH as cofactors, hydroxylates carbon 1 on
the A-ring to form calcitriol. This step is tightly regulated and is the rate-limiting step in the production of
the active hormone. The release of parathyroid hormone from the parathyroid gland results in activation of
this last step of active hormone formation.
Rickets is a disorder of young children caused by a deficiency of vitamin D. Low levels of
calcium and phosphorus in the blood are associated with skeletal deformities in these
children.
1,25-(OH)2D3 (calcitriol) is approximately 100 times more potent than 25-(OH)D3 in its actions, yet
25-(OH)D3 is present in the blood in a concentration that may be 100 times greater, which suggests that it
may play some role in calcium and phosphorus homeostasis.
The biologically active forms of vitamin D are sterol hormones and, like other steroids, diffuse
passively through the plasma membrane. In the intestine, bone, and kidney, the sterol then moves into the
nucleus and binds to specific vitamin D3 receptors. This complex activates genes that encode proteins
mediating the action of active vitamin D3. In the intestinal mucosal cell, for example, transcription of
genes that encode calcium-transporting proteins are activated. These proteins are capable of carrying
Ca2+ (and phosphorus) absorbed from the gut lumen across the cell, making it available for eventual
passage into the circulation. CLINICAL COM M ENTS
Anne J. is typical of patients with essentially normal serum triacylglycerol levels and elevated
serum total cholesterol levels that are repeatedly in the upper 1% of the general population (e.g.,
325 to 500 mg/dL). When similar lipid abnormalities are present in other family members in a pattern of
autosomal-dominant inheritance and no secondary causes for these lipid alterations (e.g., hypothyroidism)
are present, the entity referred to as familial hypercholesterolemia (FH), type IIA, is the most likely
cause of this hereditary dyslipidemia.
FH is a genetic disorder caused by an abnormality in one or more alleles responsible for the
formation or the functional integrity of high-affinity LDL receptors on the plasma membrane of cells that
normally initiate the internalization of circulating LDL and other blood lipoproteins. Heterozygotes for FH
(1 in 500 of the population) have roughly one-half of the normal complement or functional capacity of
such receptors, whereas homozygotes (1 in 1 million of the population) have essentially no functional
LDL receptors. The rare patient with the homozygous form of FH has a more extreme elevation of serum
total and LDL cholesterol than does the heterozygote and, as a result, has a more profound predisposition
to premature coronary artery disease.
Chronic hypercholesterolemia not only may cause the deposition of lipid within vascular tissues
leading to atherosclerosis but also may cause the deposition of lipid within the skin and eye. When this
occurs in the medial aspect of the upper and lower eyelids, it is referred to as xanthelasma. Similardeposits known as xanthomas may occur in the iris of the eye (arcus lipidalis) as well as the tendons of
the hands (“knuckle pads”) and Achilles tendons.
Although therapy aimed at inserting competent LDL receptor genes into the cells of patients with
homozygous FH is being designed for the future, the current approach in the treatment of heterozygotes is
to attempt to increase the rate of synthesis of LDL receptors in cells pharmacologically.
In addition to a HMG-CoA inhibitor, Anne J. was treated with ezetimibe, to achieve the
recommended decrease in her LDL. Ezetimibe blocks cholesterol absorption in the intestine, causing a
portion of the dietary cholesterol to be carried into the feces rather than packaged into chylomicrons. This
reduces the levels of chylomicron-based cholesterol and cholesterol delivered to the liver by
chylomicron remnants.
HMG-CoA reductase inhibitors, such as atorvastatin, which Anne is also taking, stimulate the
synthesis of additional LDL receptors by inhibiting HMG-CoA reductase, the rate-limiting enzyme for
cholesterol synthesis. The subsequent decline in the intracellular free cholesterol pool stimulates the
synthesis of additional LDL receptors. These additional receptors reduce circulating LDL cholesterol
levels by increasing receptor-mediated endocytosis of LDL particles.
A combination of strict dietary and dual pharmacologic therapy, aimed at decreasing the cholesterol
levels of the body, is usually quite effective in correcting the lipid abnormality and, hopefully, the
associated risk of atherosclerotic cardiovascular disease in patients with heterozygous FH.
Anne J. was treated with a statin (atorvastatin) and ezetimibe. Ezetimibe reduces the
percentage of absorption of free cholesterol present in the lumen of the gut and hence the
amount of cholesterol available to the enterocyte to package into chylomicrons.
This, in turn,
reduces the amount of cholesterol returning to the liver in chylomicron remnants. The net result is
a reduction in the cholesterol pool in hepatocytes. The latter induces the synthesis of an increased
number of LDL receptors by the liver cells. As a consequence, the capacity of the liver to increase
hepatic uptake of LDL from the circulation leads to a decrease in serum LDL levels. Despite this
decrease in LDL levels, the drug has not been shown to decrease cardiovascular events in
patients.
Ivan A. LDL cholesterol is the primary target of cholesterol-lowering therapy because both
epidemiologic and experimental evidence strongly suggest a benefit of lowering serum LDL
cholesterol in the prevention of atherosclerotic cardiovascular disease. Similar evidence for raising
subnormal levels of serum HDL cholesterol is less conclusive but adequate to support such efforts,
particularly in high-risk patients, such as Ivan A., who have multiple cardiovascular risk factors.
So far, Mr. A. has failed in his attempts to reach his diet and physical activity goals. His LDL
cholesterol level is 231 mg/dL. Based on his cardiovascular risk, he is a candidate for drug treatment. He
should be given a high-intensity HMG-CoA reductase inhibitor. A low daily dose of aspirin (81 mg)
could also be prescribed (see Chapter 31). It is important to gain early control of Mr. A.’s metabolic
syndrome before the effects of insulin resistance can no longer be reversed. Various lipid-lowering agents
are summarized in Table 32.6.Vera L. Vera L. was born with a normal female genotype and phenotype, had normal female sexual
development, spontaneous onset of puberty, and regular, although somewhat scanty, menses until the
age of 20 years. At that point, she developed secondary amenorrhea (cessation of menses) and evidence
of male hormone excess with early virilization (masculinization).
The differential diagnosis included an ovarian versus an adrenocortical source of the excess
androgenic steroids. A screening test to determine whether the adrenal cortex or the ovary is the source of
excess male hormone involves measuring the concentration of DHEAS in the patient’s plasma because the
adrenal cortex makes most of the DHEA and the ovary makes little or none. Vera’s plasma DHEAS level
was moderately elevated, identifying her adrenal cortices as the likely source of her virilizing syndrome.
If the excess production of androgens is not the result of an adrenal tumor, but rather the result of a
defect in the pathway for cortisol production, the simple treatment is to administer glucocorticoids by
mouth. The rationale for such treatment can be better understood by reviewing Figure 32.21. If Vera L.
has a genetically determined partial deficiency in the P450C11 enzyme system needed to convert 11-
deoxycortisol to cortisol, her blood cortisol levels would fall. By virtue of the normal positive feedback
mechanism, a subnormal level of cortisol in the blood would induce the anterior pituitary to make more
ACTH. The latter would not only stimulate the cortisol pathway to increase cortisol synthesis to normal
but, in the process, would also induce increased production of adrenal androgens such as DHEA and
DHEAS. The increased levels of the adrenal androgens (although relatively weak androgens) would
cause varying degrees of virilization, depending on the severity of the enzyme deficiency. The
administration of a glucocorticoid by mouth would suppress the high level of secretion of ACTH from the
anterior pituitary gland that occurs in response to the reduced levels of cortisol secreted from the adrenal
cortex. Treatment with prednisone (a synthetic glucocorticoid), therefore, will prevent the ACTH-induced
overproduction of adrenal androgens. However, when ACTH secretion returns to normal, endogenous
cortisol synthesis falls below normal. The administered prednisone brings the net glucocorticoid activity
in the blood back to physiologic levels. Vera’s adrenal androgen levels in the blood returned to normal
after several weeks of therapy with prednisone (a synthetic glucocorticoid). As a result, her menses
eventually resumed and her virilizing features slowly resolved.Because Vera’s symptoms began in adult life, her genetically determined adrenal hyperplasia is referred to as a nonclassic or atypical form of the disorder. A more severe enzyme deficiency leads to the
“classic” disease, which is associated with excessive fetal adrenal androgen production in utero and
manifests at birth, often with ambiguous external genitalia and virilizing features in the female neonate.
BIOCHEM ICAL COM M ENTS
Drugs used to treat certain aspects of the metabolic syndrome improve insulin sensitivity and
regulate lipid levels through modulation of the pathways discussed in Chapters 29 through 32.
These drugs work by modifying the regulatory pathways that have been discussed so far with regard to
carbohydrate and lipid metabolism.
Metformin. Metformin has been used for more than 30 years as a treatment for type 2 diabetes.
Metformin reduces blood glucose levels by inhibiting hepatic gluconeogenesis, which is active in
these patients because of the liver’s resistance to the effects of insulin. Metformin also reduces lipid
synthesis in the liver, which aids in modulating blood lipid levels in these patients.
Metformin accomplishes its effects by activating the AMP-activated protein kinase (AMPK). It does
so through activation of an upstream protein kinase, LKB1, via an unknown mechanism. As has been
discussed previously, AMPK, when active, phosphorylates and reduces the activity of acetyl-CoA
carboxylase (required for fatty acid synthesis) and HMG-CoA reductase (reducing the biosynthesis of
cholesterol). Activation of AMPK also activates glucose uptake by the muscle (see Chapter 45), which is
significant for reducing circulating blood glucose levels.
The LKB1 protein is a tumor suppressor; loss of LKB1 activity leads to Peutz-Jeghers syndrome (PJS). PJS exhibits the early development of hamartomatous polyps (benign polyps) in the gastrointestinal tract and an increased incidence of carcinomas at a relatively young
age. LKB1 regulates the activity of 14 kinases that include, and are similar to, the AMPK. Loss of
the normal regulation of these kinases, because of the absence of LKB1 activity, significantly
contributes to tumor formation.
The activation of AMPK also leads to a cascade of transcriptional regulation that reduces the liver’s
ability to undergo both gluconeogenesis and lipogenesis. Activated AMPK
phosphorylates a coactivator
of the CREB transcription factor named transducer of regulated CREB activity 2 (TORC2) (Fig. 32.25).
When TORC2 is phosphorylated, it is sequestered in the cytoplasm, and CREB becomes very inefficient
at transcribing a gene that is required to upregulate genes that code for the enzymes involved in
gluconeogenesis. This important transcriptional coactivator is named peroxisome proliferator-activated
receptor-γ coactivator 1α (PGC1α). PGC1α participates in the transcriptional activation of key
gluconeogenic enzymes, such as glucose 6-phosphatase and phosphoenolpyruvate carboxykinase
(PEPCK). Thus, in the presence of metformin, hepatic gluconeogenesis is reduced and muscle uptake of
blood glucose is enhanced, leading to stabilization of blood glucose levels. The physiologic regulators of
LKB1 have yet to be identified.Activation of AMPK also inhibits liver lipogenesis. In addition to phosphorylating and inhibiting
acetyl-CoA carboxylase activity (which reduces malonyl-CoA levels, leading to reduced fatty acid
synthesis and enhanced fatty acid oxidation), AMPK activity decreases the transcription of key lipogenic
enzymes, including fatty acid synthase and acetyl-CoA carboxylase. The reduced transcriptional activity
is mediated via an AMPK inhibition of the transcription of SREBP-1, which in addition to regulating the
transcription of HMG-CoA reductase, also regulates the transcription of other lipogenic enzymes. The
AMPK is discussed in more detail in the “Biochemical Comments” section of Chapter 34.
Fibrates. The fibrates are a class of drugs used to decrease lipid levels (principally triglycerides)
in patients. A major target of the fibrates is peroxisome proliferator activated receptor-α (PPARα).
Fibrate binding to PPARα activates this transcription factor, which then leads to the transcription of a
multitude of genes that degrade lipids. These targets include the genes for fatty acid transport proteins (so
there is an enhanced rate of fatty acid transport into cells), fatty acid translocase (to increase
mitochondrial uptake of the fatty acids), long-chain fatty acyl-CoA synthetase (activation of the fatty acids
in the cytoplasm), and carnitine–palmitoyltransferase I (which enhances the uptake of fatty acids into the
mitochondria). In addition, PPARα activation enhances LPLexpression, represses apoCIII expression
(apoCIII inhibits the apoCII activation of LPL), and stimulates apoAI and apoAII synthesis, the major
proteins in HDL. These transcriptional changes all lead to enhanced fat use and a reduction of circulating
lipoprotein particles.
Thiazolidinediones. A third class of drugs used for the treatment of insulin resistance and type 2
diabetes mellitus is the thiazolidinediones (TZDs), which activate the PPARγ class of transcription
factors. PPARγ is expressed primarily in adipose tissue. This transcription factor is responsible for
activating the transcription of adiponectin (see Chapter 31, Section VIII.B), leading to increased
circulating adiponectin levels. The increase in adiponectin reduces the fat content of the liver and
enhances insulin sensitivity via an AMPK-dependent pathway. Thiazolidinediones also lead to a
reduction in plasma free fatty acid levels, which leads to enhanced insulin
sensitivity (see the
“Biochemical Comments” in Chapter 31).KEY CONCEPTS
Cholesterol regulates membrane fluidity and is a precursor of bile salts, steroid hormones (such as
estrogen and testosterone), and vitamin D.
Cholesterol, because of its hydrophobic nature, is transported in the blood as a component of
lipoproteins.
Within the lipoproteins, cholesterol can appear in its unesterified form in the outer shell of the
particle or as cholesterol esters in the core of the particle.
De novo cholesterol synthesis requires acetyl-CoA as a precursor, which is initially converted to
HMG-CoA. The cholesterol synthesized in this way is packaged, along with triglyceride, into VLDL
in the liver and then released into circulation.
The conversion of HMG-CoA to mevalonic acid, catalyzed by HMG-CoA reductase, is the regulated and rate-limiting step of cholesterol biosynthesis.
In the circulation, the triglycerides in VLDL are digested by lipoprotein lipase, which converts the
particle to IDL and then to LDL.
IDL and LDL bind specifically to receptors on the liver cell, are internalized, and the particle
components are recycled.
A third lipoprotein particle, HDL, functions to transfer apolipoprotein E and apolipoprotein CII to
nascent chylomicrons and nascent VLDL.
HDL also participates in reverse cholesterol transport, the movement of cholesterol from cell
membranes to the HDL particle, which returns the cholesterol to the liver. Atherosclerotic plaques are associated with elevated levels of blood cholesterol levels. High levels
of LDL are more strongly associated with the generation of atherosclerotic plaques, whereas high
levels of HDL are protective because of their participation in reverse cholesterol transport.
Bile salts are required for fat emulsification and micelle formation in the small intestine.
Bile salts are recycled via the enterohepatic circulation, forming the secondary bile acids in the
process.
The steroid hormones are derived from cholesterol, which is converted to pregnenolone, which is
the precursor for the mineralocorticoids (such as aldosterone), the glucocorticoids (such as
cortisol), and the sex steroids (such as testosterone and estrogen). Lipid-lowering drugs act on a variety of targets within liver, intestine, and adipocytes.
Diseases discussed in this chapter are summarized in Table 32.7.REVIEW QUESTIONS—CHAPTER 32
1.The statins are the major class of medications used to lower elevated serum cholesterol by initially
inhibiting the major rate-limiting step of cholesterol synthesis. Which metabolite of the pathway
would accumulate under conditions of taking a statin? A. Acetoacetyl-CoA
B. HMG-CoA C. Mevalonate D. Squalene
E. Steroid ring
2.Cholesterol, and its precursors and products, have a variety of functions within cells. Which one
statement correctly describes a function of a cholesterol precursor, cholesterol itself, or a product
derived from cholesterol?
A.Cholesterol is hydrophilic.
B.Steroid hormones are precursors of cholesterol.
C.Precursors of cholesterol can be converted to vitamin D.
D.Cholesterol can appear in its free unesterified form in the core of lipoprotein particles.
E.Malonyl-CoA is the major precursor of cholesterol synthesis.
3. A new patient is being evaluated for cardiovascular disease. The values for his lipid panel are a
total cholesterol of 400 mg/dL, an HDL reading of 35 mg/dL, and a triglyceride reading of 200
mg/dL. What would be his calculated LDL cholesterol reading?
A.165
B.193
C.205
D.325
E.3654. Which one of the following apolipoproteins acts as a cofactor activator of the enzyme LPL?
A.ApoCIII
B.ApoCII
C.ApoB-100
D.ApoB-48s
E.ApoE
5. Which one of the following sequences places the lipoproteins in the order of most dense to least
dense?
A.HDL/VLDL/chylomicrons/LDL
B.HDL/LDL/VLDL/chylomicrons
C.LDL/chylomicrons/HDL/VLDL
D.VLDL/chylomicrons/LDL/HDL
E.LDL/chylomicrons/VLDL/HDL
6. Which one of the following would you expect to observe in a patient lacking microsomal triglyceride
transfer protein (MTP) after eating a normal diet, in which each meal consisted of 30% fat?
A.Constipation
B.Elevated chylomicrons
C.Steatorrhea
D.Elevated VLDL
E.Elevated IDL
7. Patients with elevated serum LDL levels (>120 mg/dL) are first encouraged to reduce these levels
through a combination of diet and exercise. If this fails, they are often prescribed statins. The key for
statin treatment reducing circulating cholesterol levels is which one of the following?
A.Reduced synthesis of chylomicrons
B.Increased activity of LPL
C.Reduced synthesis of HDL
D.Upregulation of LDL receptors
E.Increased activity of CETP
8. A consequence of abetalipoproteinemia is a fatty liver (hepatic steatosis). This occurs because of
which one of the following?
A.Inability to produce VLDL
B.Inability to produce chylomicrons
C.Inability to produce HDL
D.Inability to produce triglyceride
E.Inability to produce LPL
9. Hormones are typically synthesized in one type of tissue, often in response to the release of a
stimulatory hormone. Which one of the following correctly matches a hormone with its stimulatory
hormone and its site of synthesis?
A.Cortisol, ACTH, adrenal cortex
B.Aldosterone, ACTH, adrenal cortex
C.Testosterone, FSH, Leydig cellsD. Estrogen, LH, ovarian follicle
E.Progesterone, LH, ovarian follicle
10. Because the steroid nucleus cannot be degraded by the human body, excretion of bile salts in stool
serves as a major route of removal of steroids from the body. Which one of the following must occur
to bile salts in order for bile salts to be excreted in the stool?
A.Intestinal bacteria deconjugate bile salts.
B.Intestinal bacteria conjugate bile salts.
C.ATP and coenzyme Q conjugate bile salts.
D.ATP and coenzyme A deconjugate bile salts.
E.Enterohepatic circulation occurs at 100% efficiency.
ANSWERS TO REVIEW QUESTIONS
1.The answer is B. The statins inhibit the enzyme HMG-CoA reductase, which reduces HMG-CoA
to mevalonic acid. Therefore, HMG-CoA would be the metabolite that accumulates. The pathway
is initiated with acetyl-CoA, which then forms acetoacetyl-CoA and then HMG-CoA. The HMGCoA is reduced to mevalonic acid, which is then converted to isoprene units, to farnesyl units,
geranyl units, and finally to squalene, which is converted to cholesterol.
2.The answer is C. Cholesterol is absolutely insoluble in water (it is very hydrophobic). It is a
precursor of both the bile acids and the steroid hormones. Precursors of cholesterol are converted
to ubiquinone, dolichol, and cholecalciferol (the active form of vitamin D). Cholesterol can
appear unesterified in the outer shell of lipoproteins but as cholesterol esters in the core of such
particles. Malonyl-CoA is the precursor of fatty acids; acetyl-CoA is the precursor for all the
cholesterol carbons.
3.The answer is D. Total cholesterol is equal to the lipoproteins that carry it because cholesterol
cannot freely float in blood serum. The total cholesterol would then be composed of the
cholesterol content of HDL, VLDL, and LDL. Under fasting conditions, taking the triglyceride
concentration and dividing it by 5 can estimate the cholesterol content of VLDL. Thus, for this
patient, the HDLis 35 mg/dL, and the VLDLis 40 mg/dL. The total cholesterol is 400 mg/dL,
indicating that the calculated LDLcholesterol is 400 − 75, or 325 mg/dL.
4.The answer is B. ApoCIII appears to inhibit the activation of LPL. ApoE acts as a ligand in
binding several lipoproteins to the LDLreceptor, the LRP, and possibly to a separate apoE
receptor. ApoB-48 is required for the normal assembly and secretion of chylomicrons from the
small bowel, whereas apoB-100 is required in the liver for the assembly and secretion of VLDL.
ApoCII is the activator of LPL.
5.The answer is B. Because chylomicrons contain the most triacylglycerol, they are the least dense
of the blood lipoproteins. Because VLDLcontains more protein, it is denser than chylomicrons.
Because LDLis produced by degradation of the triacylglycerol in VLDL, LDLis denser than
VLDL. HDLis the densest of the blood lipoproteins. It has the most protein and the least
triacylglycerol.
6.The answer is C. MTP is required for the synthesis of nascent chylomicrons and VLDL. In the
intestine, the lack of MTP activity leads to an accumulation of lipid in the intestinal epithelial,such that further lipid is not transported in from the lumen.