Endo/Repro - Biochemistry - Cholesterol & Steroid Hormone Synthesis; Vitamins Flashcards
Which organ is the main regulator of body cholesterol?
The liver
What structure helps transport cholesterol to the liver from the gut?
What protein helps transport cholesterol from the liver to the extrahepatic tissues?
What protein helps transport cholesterol to the liver from the extrahepatic tissues?
Chylomicrons
VLDL
HDL
Which is the hydrophilic portion of a cholesterol molecule?
Which is the hydrophobic portion of a cholesterol molecule?
The 3’-OH
the rest of the molecule
True/False.
Cholesterol is a polar molecule made of 4 rings + a 7 carbon tail attached to the 18’-carbon.
False.
Cholesterol is a polar molecule made of 4 rings + an 8 carbon tail attached to the 17‘-carbon.
What is the initial precursor used to synthesize cholesterol?
Acetyl-CoA
Describe the basic steps (in simplified form) of cholesterol synthesis.
Acetyl-CoA + 3-carbon molecule –> 5-carbon isoprene
5 isoprenes –> 30-carbon squalene
Cyclization –> 27-carbon, 4-ring cholesterol
What are the major intermediates of cholesterol synthesis?
(18) Acetyl-CoA –>
(6) HMG-CoA –>
(6) mevalonate –>
(6) activated isoprene –>
(1) squalene –>
(1) cholesterol
Besides cholesterol, what other metabolites is activated isoprene (pentenyl pyrophosphate) potentially used to synthesize?
Vitamins ADEK,
dolichol (used in N-linked glycosylation),
quinone electron carriers
What is the substrate and product of the reaction mediated by HMG-CoA reductase?
HMG –> Mevalonate
How do statins inhibit HMG-CoA reductase?
Via what type of inhibition?
They are structural analogs;
competitive inhibition
The complex process of squalene cyclizing and hydroxyl groups being added to the subsequent cholesterol molecule is completed by enzymes known as _____________.
Monooxygenases
Describe the allosteric regulation of HMG-CoA reductase.
High ATP –> increased protein phosphatase activity –>
increased HMG-CoA reductase activity
Low ATP –> increased AMP-activated protein kinase (AMPK) activity –>
decreased HMG-CoA activity
For what purpose does high ATP levels stimulate HMG-CoA reductase activity?
A period of high ATP levels (e.g. the non-fasting state) is the time for membrane repair and compound synthesis
What effect does insulin have on HMG-CoA reductase?
What effect do glucagon/epinephrine have on HMG-CoA reductase?
Increased activity;
decreased activity
What effect does dephosphorylation have on HMG-CoA reductase?
What effect do phosphorylation have on HMG-CoA reductase?
Increased activity;
decreased activity
Describe the upregulation of HMG-CoA expression.
Low [cholesterol]:
SREBP-SCAP moves from the ER to the Golgi –>
SREBP moves to the nucleus and binds SRE –>
Transcription increases
What part of the upregulation of HMG-CoA reductase (shown below) is inhibited by high [cholesterol/sterol]? How?
SREBP-SCAP moves from the ER to the Golgi –>
SREBP moves to the nucleus and binds SRE –>
Transcription increases
Increased [cholesterol] (or [sterol] in general) causes increased binding of the SREBP-SCAP complex to the protein insig in the ER, preventing movement to the Golgi
Describe what happens after a chylomicron is formed in the enterocytes.
It moves into a lacteal/the lymphatic system and to the bloodstream;
peripheral tissue liproprotein lipase cleaves the TGs into free fatty acids for uptake;
the remaining chylomicron remnant travels to the liver to deliver its cholesterol
Describe the frunctions/relationship between VLDL and LDL.
VLDLs: leave liver to drop off TGs/FAs to periphery
VLDLs: become LDLs once they are depleted in TGs/FAs (cholesterol:TG ratio increases)
LDLs deliver cholesterol to periphery
What are the four main lipoprotein complexes?
Chylomicrons
VLDL
LDL
HDL
Name the basic function of each of the following lipoprotein complexes:
Chylomicron
Chylomicron remnant
VLDL
LDL
HDL
Chylomicron - deliver fatty acids to the periphery
Chylomicron remnant - deliver remaining cholesterol to the liver
VLDL - deliver fatty acids to the periphery
LDL - deliver cholesterol to the periphery
HDL - return cholesterol to the liver
Describe the various relationships between the various lipoprotein complexes (chylomicrons, chylomicron remnants, VLDLs, LDLs, HDLs)
What is indicated by high LDL levels?
What is indicated by high HDL levels?
High cholesterol;
cholesterol being cleared from the periphery
List the four main lipoprotein complexes in order of increasing density.
Chylomicrons >
VLDLs >
LDLs >
HDLs
How is cholesterol moved into the interior regions of a chylomicron or other lipoprotein complex if it is a polar molecule?
How does this happen?
It first must be esterified to a fatty acid (at the cholesterol’s 3’-carbon);
via phosphatidylcholine(lecithin):cholesterol acetyltransferase (LCAT or PCAT)
How does the enzyme LCAT (PCAT) aid in cholesterol transport?
It esterifies cholesterol so it is more hydrophobic
(and better able to diffuse into the lipoprotein complex interiors)
What type of protein is on the outside of lipoprotein complexes, communicating with the external environment and changing the way the complex interacts with tissues?
Apolipoproteins
Where will an unesterified cholesterol molecule be found in a chylomicron?
Where will an esterified cholesterol molecule be found in a chylomicron?
The periphery (polar head facing outside);
the interior (hydrophobic molecule)
What percentage of each of the following lipoprotein complexes is made up of triglycerides?
Chylomicrons
VLDLs
HDLs
85%
50%
4%
Name any intermediates in the synthesis of progesterone from cholesterol.
Cholesterol –> pregnenolone –> progesterone
After cholesterol is converted to pregnonelone and then progesterone, what three major pathways can it then follow?
Conversion to either:
glucocorticoids, mineralocorticoids, or testosterone
The corpus luteum is responsible for the synthesis of what major hormone(s)?
Progesterone,
estradiol
What effect do mineralocorticoids have on the kidneys?
Increased Na+ reabsorption;
increased K+/H+ excretion
What effect can anabolic steroids have on an individual’s lipid profile?
What class has the opposite effect?
Increased LDL, decreased HDL;
estrogens
Describe some of the generic side effects of improper anabolic steroid use.
Cancer (liver, kidney), jaundice, fluid retention, high blood pressure, an increase in LDL and decreases in HDL, aggression, depression, acne, trembling
Describe the gender-specific effects of improper anabolic steroid use.
Males: premature baldness, gynecomastia, testicular atrophy, and infertility
Females: premature baldness, a deeper voice, hirsutism, clitoromegaly, and oligomenorrhea
What effect can anabolic steroid use during pregnancy have on a male fetus?
And a female fetus?
Female features;
male features
True/False.
Mineralocorticoids aid in the metabolism of carbohydrates, proteins, and lipids.
False.
Glucocorticoids aid in the metabolism of carbohydrates, proteins, and lipids.
True/False.
Glucocorticoids have opposing effects in the liver and in adipose tissue.
True.
The opposing effects of glucocorticoids on the liver and adipose tissue centers around what enzyme?
Phosphoenolpyruvate carboxykinase
(increased activity in the liver; decreased activity in adipose)
What are the effects of glucocorticoids increasing phosphoenolpyruvate carboxykinase activity in the liver and decreasing it in the adipose?
Liver: Increased gluconeogenesis and glyceroneogenesis
Adipose: Decreased glycerol 3-phosphate synthesis and subsequent decreased fatty acid uptake
(triglyceride synthesis inhibited)
How do increased glucocorticoids levels contribute to insulin resistance?
Increased liver PEPCK activity and decreased adipose PEPCK activity –>
increased serum free fatty acids –>
dampened carbohydrate metabolism
True/False.
The insulin resistance in T2DM is at least partially due to elevated serum fatty acids inibiting proper glucose metabolism.
True.
What does the peroxisome proliferator-activated receptor γ do?
What class of medication activates this receptor?
Increases adipose phosphoenolpyruvate carboxykinase activity;
thiazolidinediones (glitazones)
What effect do thiazolidinediones (glitazones) exert on individuals with T2DM?
Via what mechanism?
Increased insulin sensitivity;
PPAR-γ receptor –> increased adipose PEPCK activity –> increased TG synthesis –> improvement of the lipid profile
True/False.
Thiazolidinediones (glitazones) and glucocorticoids have basically the same effect on the body.
False.
Thiazolidinediones (glitazones) decrease serum free fatty acids and increase insulin sensitivity.
Glucocorticoids increase serum free fatty acids and decrease insulin sensitivity.
What particular effects may present in a newborn if cholesterol biosynthesis is disrupted during embryonic development?
Holoprosencephaly;
genitourinary abnormalities
What axis of the neural tube is abnormal in cases of holoprosencephaly?
Ventral-dorsal
True/False.
Holoprosencephaly may display a wide range of variability.
True
(anything from lethality to a single central incisor)
What genetic defect is often indicated in holoprosencephaly?
What is its inheritability?
SHH;
autosomal dominant
What neural effect will result if the SHH gene is disrupted during development?
Holoprosencephaly
What role does the SHH gene play in neural tube development?
Regulation of the ventral-dorsal axis
What lipid is necessary for proper functioning of the SHH gene?
What may result if this lipid is absent during development?
Cholesterol;
holoprosencephaly
What is the basic etiology of Smith-Lemli-Opitz syndrome?
What is its inheritance pattern?
Bile acid / cholesterol deficiency
(huge increase in 7-dehydrocholesterol);
autosomal recessive
Describe the clinical presentation of a newborn with Smith-Lemli-Opitz syndrome.
CNS malformations (e.g. microcephaly), severe mental retardation;
cleft palate, anteverted nares, micrognathia;
polydactyly;
genital and cardiac abnormalities
What enzyme of cholesterol metabolism is deficient in Smith-Lemli-Opitz syndrome?
What metabolite builds up?
Which are deficient?
7-dehydrocholesterol reductase;
7-dehydrocholesterol;
bile acids, cholesterol
What gene is likely affected by the cholesterol deficiency seen in Smith-Lemli-Opitz syndrome?
SHH
True/False.
Many disorders of cholesterol synthesis have accompanying adrenal and gonadal insufficiencies.
True.
What is desmosterolosis?
What is deficient?
What is the buildup product?
A disorder of cholesterol synthesis;
lack of cholesterol –> disrupted SHH action;
desmosterol
True/False.
Phospholipids are essential to normal SHH (Sonic the Hedgehog gene) function.
False.
Cholesterol is essential to normal SHH function.
Where are steroid hormone receptors located?
Intracellularly
(in the nucleoplasm, nuclear membrane, or cytoplasm)
List the five classes of steroid hormone.
Progestins,
androgens,
estrogens,
glucocorticoids,
mineralocorticoids
The monooxygenases involved in cholesterol and steroid hormone synthesis are part of what enzyme system?
The cytochrome P450 system
What are the three domains of any steroid hormone nuclear receptor?
- A central DNA-binding region
- A ligand-binding domain
- A variable region (often regulatory)
What are the two types of steroid hormone nuclear receptor?
Cholesterol-derived (Type I)
Non-cholesterol-derived (Type II)
Which steroid hormone nuclear receptors are type I (cholesterol-derived)?
Estrogen receptor
Progesterone receptor
Glucocorticoid receptor
Mineralocorticoid receptor
Which steroid hormone nuclear receptors are type II (cholesterol-derived)?
Thyroxine receptor
Retinoic acid receptor
Vitamin D receptor
Where are type I steroid hormone receptors when not in-use?
Where are type II steroid hormone receptors when not in-use?
In the cytoplasm bound to an inhibitory ligand (often a heat-shock protein);
bound to DNA + a repressor
How many type I steroid hormone receptors does it take to initiate a change in gene expression?
2
(a pair of homodimers + coactivators + RXR sequence)
Type I steroid hormone receptors typically function as _____dimers.
Type II steroid hormone receptors typically function as _____dimers.
Homo-;
hetero-
What are the three receptor types that are typically clincally relevant in breast cancer?
ER (nuclear receptor)
PR (nuclear receptor)
HER-2/Neu (receptor tyrosine kinase)
What drug can be used to block estrogen receptors in ER+ breast cancer?
Tamoxifen