Regulación del metabolismo

Dr. Ernesto Vargas-Méndez, PhD.

Escuela de Medicina, UCR
Dep. Bioquímica
Balance energético
Favorable
Positivo

Producción

Consumo

Desfavorable
Negativo
¿Por qué regular o modular el metabolismo?

Trabajo (W)

Δ Energía

Producción Homeostasis ΔS
Consumo

Sobrevida
Regulación del Metabolismo

• Alosterismo
• Modificación covalente de enzimas
• Concentración de enzimas y receptores
• Compartimentalización
 These neurons produce the short peptide hormones oxytocin and vasopressin
(Fig. 23-10), which move down the axon to the nerve endings in the pituitary,
where they are stored in secretory granules to await the signal for their
release.

Sistema
endocrino

FIGURE 23-7 The major endocrine glands. The glands are shaded pink.
 Eje
hipotálamo-
Hipófisis

FIGURE 23-9 Neuroendocrine origins of hormone signals. Location of the

hypothalamus and pituitary gland and details of the hypothalamus-pituitary
Cascada de regulación hormonal
 Glándula
suprarenal y
catecolaminas
Páncreas endocrino

FIGURE 23-27 The endocrine system of the pancreas. The pancreas

contains both exocrine cells (see Fig. 18-3b), which secrete digestive enzymes
in the form of zymogens, and clusters of endocrine cells, the islets of
Langerhans. The islets contain α, β, and δ cells (also known as A, B, and D
 peptide” (C-peptide) and a few small remnants, resulting in the formation of biolog- chronic fashion.
ically active insulin (see Fig. 26.10). Zinc ions are also transported in these storage
vesicles. Cleavage of the C-peptide decreases the solubility of the resulting insulin,
which then coprecipitates with zinc. Exocytosis of the insulin storage vesicles from
the cytosol of the "-cell into the blood is stimulated by rising levels of glucose in
the blood bathing the "-cells.

Insulina Leu
Pro Gln
20
Leu Ser Gly Ala Gly Pro
Gly Gly
Ala Gly
Leu Leu
Glu
C-Peptide Glu
Val
Gly
Ser Gln

Leu Gly
31
Gln Val

Lys Gln
Arg Leu
Gly
Asp
Ile Glu
Val COOH
NH2 Asn Ala
21
Glu Cys
Glu 1
Phe Gln S A-Chain Tyr
Val Cys S Asn Arg
Cys Glu Arg
Asn Thr Leu
Ser Ile
Cys Ser Leu Tyr
Gln S Thr
Gln S Lys 30
His 10
Leu
S Pro
Insulin Thr
Cys S Tyr
Gly Phe
Ser B-Chain Phe
His Gly
Leu Arg
Val Glu Glu
10 Ala Leu Tyr Gly
Leu Val Cys
20

FIG. 26.10. Cleavage of proinsulin to insulin. Proinsulin is converted to insulin by proteolytic cleavage, which removes the C-peptide and a
few additional amino acid residues. Cleavage occurs at the arrows. (From Murray RK, Granner DK, Mayer PA, et al. Harper’s Biochemistry.
23rd ed. Stanford, CT: Appleton & Lange; 1993:560.)

Lieberman_Ch26.indd 483 01/09/12 8:59 PM

Estímulo para la secreción de glucagón
 Glucose has a special role in metabolic homeostasis. Many tissues (e.g., the brain,
red blood cells, kidney medulla, exercising skeletal muscle) depend on glycolysis for
all or a part of their energy needs. As a consequence, these tissues require uninter-
rupted access to glucose to meet their rapid rate of ATP use. In the adult, a minimum
of 190 g glucose is required per day, approximately 150 g for the brain and 40 g
for other tissues. Significant decreases of blood glucose lower than 60 mg/dL limit
CHAPTER 26 ■ BASIC CONCEPTS IN THE REGULATION OF FUEL METABOLISM 481

Visión general High-

FuelLiver
de la regulación
carbohydrate
Glycogen
Insulin meal
– +
stores

sistémica del
+ Glucagon 120
Blood Glucose

mg/dL
– +
fuel Growth + Stress
100
Glucose

metabolismo
Fatty acids 80
hormones
Amino
acids
Dietary Fuels: 120
Glucose
• Carbohydrate Neuronal Blood 80
signals

µU/mL
fuel Insulin
• Fat
• Protein 40
Fatty acids Fatty acids No
effect
0
+
Skeletal
Blood
Triacylglycerols muscle
fuel Fuel utilization 120
Adipocyte Glucagon

pg/mL
110

ATP 100
FIG. 26.7. Major sites of glucagon action in fuel metabolism. !, pathways stimulated by
glucagon; ", pathways inhibited by glucagon. 90
Cell function 60 0 60 120 180 240
Minutes

FIG. 26.5.by stimulating

Signals that gluconeogenesis from lactate,
regulate metabolic glycerol, and
homeostasis. The amino
majoracids
stress(seehormones are Blood glucose, insulin, and glu-
FIG. 26.8.
Chapter 31); and,
epinephrine and cortisol. in conjunction with decreased insulin, by mobilizing fatty acids cagon levels after a high-carbohydrate meal.
from adipose triacylglycerols to provide an alternate source of fuel (see Chapter 23
and Fig. 26.7). Its sites of action are principally the liver and adipose tissue; it has Bea Selmass’s studies confirmed
no influence on skeletal muscle metabolism because muscle cells lack glucagon that her fasting serum glucose lev-
receptors. The message carried by glucagon is that “glucose is gone”; that is, the els were below normal. She contin-
current supply of glucose is inadequate to meet the immediate fuel requirements ued to experience the fatigue, confusion, and
of the body. blurred vision she had described on her first
The release of insulin from the !-cells of the pancreas is dictated primarily by office visit. These symptoms are referred to as
 proteins. Hemoglobin A (HbA), one of the by stimulating the release of glucose from liver glycogen (see Chapter 28)
roteins that becomes glycosylated, forms
bA1c (see Chapter 7). Ann Sulin’s high levels
HbA1c (14% of the total HbA, compared with
e reference range of 4.7% to 6.4%) indicate
Glycogen Liver
at her blood glucose has been significantly
evated over the last 12 to 14 weeks, the half- + –
–
Protein
+
e of hemoglobin in the bloodstream.
Glucose
All membrane and serum proteins exposed
Hiperglicemia:
+
high levels of glucose in the blood or inter-
Fatty acids
itial fluid are candidates for nonenzymatic

Efecto de la
ycosylation. This process distorts protein
ructure and slows protein degradation, which VLDL
Amino
acids
+
Protein

Insulina
+
ads to an accumulation of these products in Glucose CO2
arious organs, thereby adversely affecting Glycogen
+
rgan function. These events contribute to Fatty acids Skeletal
e long-term microvascular and macrovascu- muscle
r complications of diabetes mellitus, which – +

clude diabetic retinopathy, nephropathy, and Triacylglycerols

europathy (microvascular), in addition to cor- Adipocyte
nary artery, cerebral artery, peripheral artery
sease, and atherosclerosis (macrovascular).
FIG. 26.6. Major sites of insulin action on fuel metabolism. VLDL, very low-density lipo
protein; !, stimulated by insulin; ", inhibited by insulin.
 CHAPTER 26 ■ BASIC CONCEPTS IN TH

Glycogen
Liver

– +

Glucose +
–

Hipoglicemia: Fatty acids

Amino

Efecto del
acids
Glucose

Glucagón
Fatty acids Fatty acids No
effect
+
Skeletal
Triacylglycerols muscle
Adipocyte

FIG. 26.7. Major sites of glucagon action in fuel metabolism. !, pathways stimulated by
glucagon; ", pathways inhibited by glucagon.
 plasma membrane of target cells for this hormone. The binding to the
Glycogen synthesis
Active glycolysis be considered as totally cific receptors
separate by glucagon
from pathways involving amino acid andstimulates
fatty the synthesis of the intracellula
acid metabolism (Fig. V.9).
messenger, cyclic adenosine monophosphate
Intertissue balance in the use and storage of glucose during fasting and feed- A (cAMP) (Fig. 26.3). cAM
Glucose
vates protein kinase A (PKA), which phosphorylates key regulatory e
ing is accomplished principally by the actions of the hormones of metabolic
homeostasis—insulin and glucagon (Fig. V.10). However, cortisol, epinephrine,
B Insulinon the other
thereby activating some
norepinephrine, and other hormones are also involved in intertissue adjustments
of supply and demand in response to changes of physiologic state.
while inhibiting others. Insulin,
Liver promotes the dephosphorylation of these key enzymes, leading to thei
tion or Blood
Glucagon release deactivation,
glucose depending on the enzyme. Changes of cAMP lev
Insulin release

induce or repress
Glycogenolysis
the synthesis of several enzymes.
Glycogen synthesis
Liver
Glucose
Gluconeogenesis
Lipolysis
Insulin binds Fattytoacid a receptor on the cell surface of insulin-sensitive t
synthesis
Triglyceride synthesis
Glucagon and initiates a Liver
Liver glycolysis cascade
glycolysis of intracellular events that differs from those
Epinephrine latedbyby
FIG. V.10. Pathways regulated glucagon.
the release Insulin
of glucagon (in response binding
to a lowering of activates both autophosphorylatio
blood glucose levels) and insulin (released in response to an elevation of blood glucose
Glycogen degradation receptor and the phosphorylation of other
levels). Tissue-specific differences occur in the response to these hormones, as detailed in
enzymes by the receptor’s
the chapters of this section. Triglyceride synthesis
Gluconeogenesis
476 kinase domain (see Chapter 11, SectionGlycogen III.B.3). The complete routes
synthesis
FIG. 26.2. Insulin and the insulin counter- signal transduction between this point Active and theglycolysis
final effects of insulin
regulatory hormones. A. Insulin promotes glu- regulatory enzymes of fuel metabolism have not yet been fully establi
cose storage, as triglyceride (TG) or glycogen.
B. Glucagon and epinephrine promote glucose B
Balance entre insulina y hormonas contrareguladoras determina el
Lieberman_Ch26.indd 476 01/09/12 8:59 PM

release from the liver, activating glycoge-

nolysis and gluconeogenesis. Cortisol will
estado metabólico sistémico
stimulate both glycogen synthesis and gluco- Liver
neogenesis.

THE WAITING ROOM

Glucose
increase in B. Red arrows connect events that result from high blood glucose;
blue arrows connect events that result from low blood glucose.

FIGURE 15-44 Difference in the regulation of carbohydrate metabolism in

liver and muscle. In liver, either glucagon (indicating low blood glucose) or
 Low Blood Glucose

Hypothalamic regulatory
center

Pituitary

ACTH

Autonomic nervous system

!-Cells
Cortex
Medulla

Adrenal Pancreas

Cortisol Epinephrine Norepinephrine Glucagon

FIG. 26.9. Major insulin counterregulatory hormones. The stress of a low blood glucose
level mediates the release of the major insulin counterregulatory hormones through neuronal
signals. Hypoglycemia is one of the stress signals that stimulates the release of cortisol,
Hipoglicemia: liberación de hormonas hiperglicemiantes o
epinephrine, and norepinephrine. Adrenocorticotropic hormone (ACTH) is released from
the pituitary and stimulates the release of cortisol (a glucocorticoid) from the adrenal cortex.

contrareguladoras
Neuronal signals stimulate the release of epinephrine from the adrenal medulla and nor-
epinephrine from nerve endings. Neuronal signals also play a minor role in the release of
glucagon. Although norepinephrine has counterregulatory actions, it is not a major counter-
regulatory hormone.
 have a priming site at position +4, which must be phosphorylated by another
protein kinase before GSK3 can act on them. (See also Figs 6-38 and 12-25b on
glycogen synthase regulation.)

Insulina y la
GSK

FIGURE 15-41 The path from insulin to GSK3 and glycogen synthase.
Insulin binding to its receptor activates a tyrosine protein kinase in the receptor,
which phosphorylates insulin receptor substrate-1 (IRS-1). The
 CHAPTER 28 ■ FORMATION AND DEGRADATION OF GLYCOGEN 521

Glucagon
(liver only) Epinephrine

+ + Glucose

Cell Adenylate Phospho-

membrane cyclase diesterase

Cytoplasm G- GTP
1
protein + ATP AMP Glucose
cAMP
Glucokinase

Protein Regulatory Glucose 6-phosphate

kinase A 2 subunit-cAMP

Glucagón y
(inactive)
Glycogen
Pi Phosphorylase synthase– P
kinase ATP

la Glucógeno
(inactive) Glucose 1-phosphate
(inactive)
Protein ADP Protein
phosphatase 3 Active protein 5 phosphatase

sintasa
kinase A ATP
ADP Glycogen
Phosphorylase synthase Pi
kinase– P (active)
(active)

4
ATP ADP Glycogen UDP-glucose
Glycogen Glycogen Pi
phosphorylase b phosphorylase a
(inactive) (active) P
6

Pi Glucose 1-phosphate Glucose 6-phosphate

Protein
phosphatase Liver Glucose 6-
phosphatase

Blood
glucose

FIG. 28.8. Regulation of glycogen synthesis and degradation in the liver. 1. Glucagon binding to the serpentine glucagon receptor or epineph-
rine binding to a serpentine !-receptor in the liver activates adenylate cyclase via G proteins, which synthesizes cAMP from ATP. 2. cAMP binds
to PKA (cAMP-dependent protein kinase), thereby activating the catalytic subunits. 3. PKA activates phosphorylase kinase by phosphorylation.
4. Phosphorylase kinase adds a phosphate to specific serine residues on glycogen phosphorylase b, thereby converting it to the active glycogen
phosphorylase a. 5. PKA also phosphorylates glycogen synthase thereby decreasing its activity. 6. Because of the inhibition of glycogen syn-
 hypertension (high blood pressure) although corticosterone also has some GC activity. GCs, such as cortisol, were
is caused by a catecholamine-
secreting neoplasm of the adrenal medulla,
known as a pheochromocytoma. Patients with
Pancreas
this kind of tumor periodically secrete large
amounts of epinephrine and norepinephrine !-cell "-cell
into the bloodstream. Symptoms related to this – Epi
secretion include a sudden and often severe
Insulin
increase in blood pressure, heart palpitations, + Epi
Glucagon
a throbbing headache, and inappropriate and
diffuse sweating. In addition, chronic hyperse-
Liver
cretion of these catecholamines may lead to
impaired glucose tolerance or even overt dia- Glycogen
Epinefrina
betes mellitus. Describe the actions of these
(Adrenalina) y
+ Epi
hormones that lead to the significant rise in Glucose

metabolismo
glucose levels.
Glucose
del glucógeno + Epi

Glycerol
Epi
FA +
Epi +
Glycogen

TG Pyruvate
and lactate
Adipose Muscle

FIG. 43.6. Effects of epinephrine on fuel metabolism and pancreatic endocrine function.
Epinephrine (Epi) stimulates glycogen breakdown in muscle and liver, gluconeogenesis in
 Regulación de la glucólisis

FIGURE 15-19 Regulation of fructose 2,6-bisphosphate level. (a) The

cellular concentration of the regulator fructose 2,6-bisphosphate (F26BP) is
 El caso de la Glucoquinasa (hexoquinasa IV):
Regulación metabólica por
FIGURE
afinidad
15-14
tes with glucose in the nucleus by transport through the nuclear Comparison of
enzimática
the kinetic properties of hexokinase
(glucokinase) and hexokinase I. Note the sigmoidicity for hexokinase IV a
lucose causes dissociation of the regulatory protein, and
the hexokinase
much lower Km for hexokinase I. When blood glucose rises above 5 m
s the cytosol and begins to phosphorylate glucose. hexokinase IV activity increases, but hexokinase I is already operating n
Vmax and cannot respond to an increase in glucose concentration. Hexokina
I, II, and III have similar kinetic properties.

FIGURE 15-15 Regulation of hexokinase IV (glucokinase) by sequestrati

in the nucleus. The protein inhibitor of hexokinase IV is a nuclear bindi
URE 15-14 Comparison of the kinetic properties of hexokinase protein IV that draws hexokinase IV into the nucleus when the fructose
phosphate
Nelson, D. & Cox, M. 2017. concentration
Lehninger Principles in liver
of Biochemistry. is high and releases it to the cytosol when
7th ed.
cokinase) and hexokinase I. Note the sigmoidicity for hexokinase IV and
synthase by covalent alteration (see Fig. 15-41). The first two effects of
insulin increase glucose flux through the pathway (control), and the third
serves to adapt the activity of glycogen synthase so that metabolite
FIGURE levels15-14 Comparison of the kinetic properties of hexokinase IV
(glucose 6-phosphate, for example) will not change dramatically with the
(glucokinase) and hexokinase I. Note the sigmoidicity for hexokinase IV and
increased flux (regulation).
the much lower Km for hexokinase I. When blood glucose rises above 5 mM,
hexokinase IV activity increases, but hexokinase I is already operating near
Vmax and cannot respond to an increase in glucose concentration. Hexokinases
I, II, and III have similar kinetic properties.

FIGURE 15-15 Regulation of hexokinase IV (glucokinase) by sequestration

in the nucleus. The protein inhibitor of hexokinase IV is a nuclear binding
Hepatocito
protein that draws hexokinase IV into the nucleus when the fructose 6-
phosphate concentration in liver is high and releases it to the cytosol when the
glucose concentration is high.

Tejido extrahepático
La insulina aumenta la presentación de Glut4
en las membranas celulares extrahepáticas
508 SECTION V ■ CARBOHYDRATE METABOLISM

Cell membrane the liver’s role as the organ that maintains blood glucose levels. Thus, the liver
will convert glucose into other energy storage molecules only when blood glucose
Glucose levels are high, such as the time immediately after ingesting a meal. In muscle and
transporter adipose tissue, the transport of glucose is greatly stimulated by insulin. The mecha-
Insulin
nism involves the recruitment of glucose transporters (specifically, GLUT 4) from
Receptor
intracellular vesicles into the plasma membrane (Fig. 27.13). In adipose tissue, the
stimulation of glucose transport across the plasma membrane by insulin increases
its availability for the synthesis of fatty acids and glycerol from the glycolytic path-
+ way. In skeletal muscle, the stimulation of glucose transport by insulin increases its
availability for glycolysis and glycogen synthesis.

V. GLUCOSE TRANSPORT THROUGH THE BLOOD–BRAIN

BARRIER AND INTO NEURONS
A hypoglycemic response is elicited by a decrease of blood glucose concentration
to some point between 18 and 54 mg/dL (1 and 3 mM). The hypoglycemic response
is a result of a decreased supply of glucose to the brain and starts with light-
headedness and dizziness and may progress to coma. The slow rate of transport
of glucose through the blood–brain barrier (from the blood into the cerebrospinal
fluid) at low levels of glucose is thought to be responsible for this neuroglyco-
G G penic response. Glucose transport from the cerebrospinal fluid across the plasma
membranes of neurons is rapid and is not rate limiting for ATP generation from
G G glycolysis.
In the brain, the endothelial cells of the capillaries have extremely tight junc-
G G
tions, and glucose must pass from the blood into the extracellular cerebrospinal
fluid by GLUT 1 transporters in the endothelial cell membranes (Fig. 27.14) and
then through the basement membrane. Measurements of the overall process of
glucose transport from the blood into the brain (mediated by GLUT 3 on neural
G , Glucose , Glucose transporters cells) show a Km,app of 7 to 11 mM and a maximal velocity not much greater than
(GLUT4) the rate of glucose utilization by the brain. Thus, decreases of blood glucose below

FIG. 27.13. Stimulation by insulin of glu-

cose transport into muscle and adipose cells. Neural Non-neural
 Fasted state

Lipase
(inactive)
TG Blood
Protein
kinase A
+
Hormone-
Glucagón y sensitive cAMP
epinefrina en la lipase– P
movilización de (active) + Low insulin/high glucagon
ácidos grasos ATP
FA FA
Other FA FA
lipases
FA FA
Glycerol Glycerol
Adipose cell

FIG. 33.23. Mobilization of adipose triacylglycerol (TG). In the fasted state, when insu
levels are low and glucagon is elevated, intracellular cyclic adenosine monophosphate (cAM
FIGURE 17-3 Mobilization of triacylglycerols stored in adipose tissue.
When low levels of glucose in the blood trigger the release of glucagon, 1 the
pecific receptors on the cell membrane of 808
stances. Hence, blood glucose SECTION VIII ■ TISSUE METABOLISM
levels may rise
TH)-secreting cells of the anterior pituitary in patients who have a pheochromocytoma.
receptor interaction causes ACTH to be
eventually to interact with specific recep- Hemorrhage
anes of cells in the zona fasciculata and Emotions Exercise When Otto Shape was writing his list Precursors
Gluconeogenesis
The major trophic influence of ACTH on Hypoglycemia
Liver PEPCK
Infections of differential diagnoses to explain
Pain
conversion of cholesterol to pregnenolone, Cold Glycogen storage
es are derived (see Chapter 34 for the bio- exposure Trauma the clinical presentation of Corti GC + Glycogen

al cortex in response to ACTH. The con-

Sleep
Hypothalamus
Solemia, Toxins
he suddenly thought of a relatively Glucose
+ Epi
hat bathes the CRH-producing cells of the rare endocrine disorder that could explain
Acetylcholine, serotonin
ng cells of the anterior pituitary acts as a + GC
latory influence on the release of CRH and all of the presenting signs and symptoms. He Glucose
AA
vels in the blood suppress CRH and ACTH CRH made a provisional diagnosis of excessive
ate secretion. In severe stress, however, the
retion exerted by high cortisol levels in the
–
secretion of cortisol secondary to an excess
d activity of the higher portions of the axis secretion of ACTH (Cushing “disease”) or by Glycerol AA
m in liver, skeletal muscle, and adipose tis- a primary increase of cortisol production by
Pituitary
gure 43.8. Their effects on other tissues are an adrenocortical tumor (Cushing syndrome). GC + FA
l for life. Some of the nonmetabolic actions + GC
Otto suggested that resting, fasting plas-
+
ma cortisol and ACTH levels be measured at
IDS –
TG
8:00 the next morning. These studies showed
st tissues of the body. At first glance, some
Muscle
dictory (such as inhibition of glucose uptake
Cortisol that ACTHMr. Solemia’s morning plasma ACTH and
hey promote survival in times of stress.
cortisol levels were both significantly higher Adipose
RNA, and protein synthesis and stimulate
es. In response to chronic stress, GCs act than
+ the reference range. Therefore, Otto con-
the acute alarm sounds and epinephrine is Protein degradation
When GCs are elevated, glucose uptake by cluded that Mr. Solemia probably had a tumor Lipolysis Protein synthesis
polysis occurs in peripheral adipose tissue,
Adrenal gland that was producing ACTH autonomously (i.e., Glucose utilization Glucose utilization
oid cells, and muscle. The fatty acids that
r energy, and the glycerol and amino acids not subject
FIG. 43.7. Regulation of cortisol secretion. to normal feedback inhibition by
FIG. 43.8. Effects of GCs on fuel metabolism. GCs stimulate lipolysis in adipose tissue and
stimulate the release of CRH.cortisol). The high plasma levels of ACTH
production of glucose, which is converted Various factors act on the hypothalamus to
al of epinephrine stimulates liver glycogen CRH stimulates the release of amino acids from muscle protein. In liver, GCs stimulate gluconeogenesis and
the release of ACTH from the were stimulating the adrenal cortex to pro-
anterior pituitary,
s fuel to combat the acute stress. which stimulates the release of cortisol from the the synthesis of glycogen. The breakdown of liver glycogen is stimulated by epinephrine. AA,

t these effects involves binding of the ste-
ion of the steroid–receptor complex with
Cortisol
duce
adrenal cortex. Cortisol inhibits excessive
the release of amounts of cortisol. Additional amino acid; Epi, epinephrine; PEPCK, phosphoenolpyruvate carboxykinase; TG, triglyceride.
CRH and ACTH via negative feedback loops.
laboratory and imaging studies indicated that
the hypercortisolemia was caused by a benign GC response elements on DNA, transcription of genes, and synthesis of specific
ACTH-secreting adenoma of the anterior pitu- proteins (see Chapter 16, Section III.C.2). In some cases, the specific proteins
itary gland (Cushing “disease”). responsible for the GC effect are known (e.g., the induction of phosphoenolpyru-
01/09/12 9:32 PM
vate carboxykinase that stimulates gluconeogenesis). In other cases, the proteins
responsible for the GC effect have not yet been identified.

Table 43.3 Some Nonmetabolic Physiologic Actions of Glucocorticoids

 654 SECTION VI ■ LIPID METABOLISM

LDL

ACTH

Cortisol R LDL
G receptor
AC
Cholesterol

Cortisol:
ATP cAMP ester
lipase
Protein kinase A
Cholesterol

Síntesis
Endoplasmic
reticulum Cholesterol
1
Progesterone 2 Pregnenolone
3
4
11-Deoxycortisol

5
Mitochondrion
Cortisol

FIG. 34.24. Cellular route for cortisol synthesis. Cholesterol is synthesized from acetyl-
CoA or derived from low-density lipoprotein (LDL), which is endocytosed and digested