Clark Biochemistry (Exam 2)

Question 1

Define the (3) classes of complex lipids and their subclasses

Answer 1

1) TAG (Triacylglycerol) = glycerol + 3 fatty acids (FA)
2) Glycerophospholipids = glycerol backbone + phosphdiester bond of chemical grp (ex. choline, serine) at C3 position
3) Sphingolipids = ceramide backbone + another grp. (2) subclasses:
- Sphingophospholipids, which only includes Sphingomyelin = ceramide + phosphocholine
- Glycolipids = ceramide + carbohydrate

Question 2

What is the role of glycerol-3-phosphate (G-3-P), phosphatidic acid, and diacylglycerol (DAG) in TAG and glycerophospholipid synthesis?

Answer 2

Synthesis of TAG and glycerophospholipids begins w/ G-3-P and PA then DAG are intermediates in the process.

• Acetyltransferases take the two -OH (ols) and replace them w/ 2 FA at C1 and C2 to make Phosphatidic acid.
• Then, a phosphatase replaces the C3 phosphate w/ an -OH to make DAG (diacylglycerol) = glycerol + 2 FA + OH
• Finally a phosphodiester bond is formed between either choline, ehtanolamine, serine, or inositol at C3

Question 3

What are the (2) major mechanisms for the synthesis of glycerophospholipids and the end products for each?

Answer 3

Route 1: starts from DAG. And the head groups choline or ethanolamine are activated by attaching to CDP. This pathway is used to synthesize phosphatidylcholine (PC) or phosphatidylethanolamine (PE)

Route 2: starts with Phosphatidic acid, which FIRST reacts with CTP to form CDP-diacylglyercol. Then that condenses w/ a head grp to make either Phosphatidylinositol (PI) or Cardiolipin.

Question 4

List the (4) major glycerophospholipids

Answer 4

Phosphatidylcholine (PC)
Phosphatidylethanolamine (PE)
Phosphatidylinositol (PI), and
Cardiolipin

Question 5

What process is phospholipase C (PLC) involved in? How does the action of PLC generate calcium signaling in the cell?

Answer 5

PLC is one of the enzymes that does glycerophospholipid degradation (i.e. releases fatty acids). PLC cleaves the phosphoester bond at C’3 from PI making DAG + IP3.
IP3 then increases intracellular Ca and calcium signaling!

Question 6

What is the deficiency in RDS (respiratory distress syndrome)? How do you determine fetal lung maturity based on complex lipid levels?

Answer 6

Dipalmitoylphosphatidylcholine deficiency contributes to RDS, due to its ability to decrease surface tension at the air-water interface.

The PC : sphingomyelin ratio is an indicator for lung maturation. At 34 wks, PC levels rise rapidly while sphingomyelin stays constant or decreases. A ratio of 2.0 or better is a good indicator that lung surfactant levels are sufficient.

Question 7

What are the (4) sphingolipid classes and members of each class?

Answer 7

1) Phosphosphingolipids. Only member = sphingomyelin
2) Cerebrosides (neutral). Includes Glucocerebrosides, Galactocerebrosides, and Globosides
3) Sulfatide (acidic)
4) Gangliosides. Members = GM1-GM4

Question 8

What is the fundamental (overall) problem for the sphingolipidoses disorders? What is pattern of inheritance?

Answer 8

Sphingolipidoses are inherited, autosomal recessive disorders that result in a block of breakdown of sphingolipids due to either 1) enzyme deficiency in the degradation pathway, or 2) defect in activator protein of degradative enzyme.

Overall feature = ACCUMULATION of sphingolipids in cells

Question 9

What are the enzyme deficiencies in Tay-Sachs, Gaucher’s, and Niemann-Pick disorders?

Answer 9

Tay-Sachs = HexA (accum of GM2)
Gaucher's = beta-glucosidase (accum of glucocerebrosides)
Niemann-Pick = sphingomyleinase (accum of sphingomyelin)

Question 10

Classic clinical feature of Tay-Sach’s

Answer 10

cherry-red spot on the macula (which indicates the sphingolipid GM2 accumulation due to HexA deficiency)

Question 11

Classic clinical feature of Gaucher’s

Answer 11

cells w/ cytoplasm that have a “wrinkled tissue paper” appearance (which is consequence of glucocerebroside deposition due to beta-glucosidase [a glucocerebrosidase enzyme] deficiency)

Question 12

Distinguishing feature of the phosphosphingolipid class of sphingolipids

Answer 12

1 member of this class = Sphingomyelin. Is the ONLY phospho-containing sphingolipid. Has NO carbohydrate

Question 13

Distinguishing feature of the Cerebroside (Neutral) class of Sphingolipids and (3) members of this class

Answer 13

this class defined by attachment of either glucose or galactose to the ceramide backbone. Since the carb attachment has no charge, these glycosphingolipids (aka “glycolipids”) are uncharged/neutral.

(3) members = Glucocerebrosides (glucose only), Galactocerebrosides (galactose only), and Globosides (both glucose and galactose)

Question 14

Distinguishing feature of Gangliosides class of Sphingolipids and nomenclature for gangliosides

Answer 14

contain actylated sugars GlcNac, GalNac, and a NANA attachment to galactose. Members = GM1-GM4.
G = ganglioside then M (mono), D (di), or T (tri) = # of NANA attachments

Question 15

What is the function of hormone sensitive lipase (HSL)?

Answer 15

enzyme that removes FFA from TAG. This is a major control point for FA beta-oxidation in the liver and extrahepatic tissues (muscle)

Question 16

Regulation of HSL with glucagon v. insulin. Name (3) additional means of regulating HSL

Answer 16

Glucagon phosphorylates and stimulates HSL. Insulin inhibits HSL (indirectly through a phosphodiesterase).
Also:
-Catecholamines, NE > Epi stimulate HSL
-Transcriptional reg: Glucocorticoids and Thyroid hormone increase HSL mRNA and protein levels
-Caffeine stimulates HSL and counters insulin action

Question 17

How is it that HSL activity in ADIPOSE tissue controls fatty acid beta-oxidation and ketone body (KB) synthesis in the LIVER?

Answer 17

Acetyl-coA produced in the mito as a product of FA-beta-oxidation = substrate for KB synthesis. Glucagon stimulates HSL and lipolysis in adipose tissue, which releases FFA from TAG for beta-oxidation. Therefore, ketone body synthesis in the liver is dependent upon TAG metabolism in adipose.

Question 18

How do LCFA (long chain fatty acids) get transported into the mitochondria for FA-beta oxidation? Name (4) enzymes that complete this.

Answer 18

First, the FA is activated to Acyl-coA by Acyl-coA synthetase (outer membrane). Then, through a reversible exchange of CoA for carnitine, the FA is driven into the mito matrix. (3) enzymes that accomplish this, in order =
-CPT I (outer membrane), Carnitine acylcarnitine translocase (inner), and CPT II (inner)

Question 19

What are Acyl-CoA dehydrogenases? How does a defect in acyl-coA dehydrogenase lead to hypoglycemia?

Answer 19

A family of enzymes that distinguish between FA based on chain length. Are the first step in beta-oxidation. So mutations in genes encoding acyl-coA dehydrogenases lead to deficiencies in beta-oxidation. Ex. MCAD.
Hypoglycemia results from decreased ability to use FA for energy during fasting state. So muscles and other extrahepatic tissues that would be using FA now take in additional glucose leading to hypoglycemia.

Question 20

What are ketone bodies (KB) and what do they do? Name the 2 ketone bodies.

Answer 20

KB are short, 4-carbon carboxylic acids composed of two acetyl-coAs. Function = shuttle Acetyl-coA from the liver to extrahepatic tissues as a way to supply energy during fasting. Those tissues oxidize KB back to acetyl-coA to enter the TCA cycle and make ATP.

(2) KB = Acetoacetate and Beta-hydroxybutyrate.

Question 21

How is the synthesis of ketone bodies (KB) dysregulated in T1DM?

Answer 21

T1DM leads to OVERproduction of ketone bodies. Due to less insulin, missing the inhibition of HSL. So continued activity of HSL means increased levels of FA to generate Acetyl-coAs. These acetyl-coAs are substrates for KB synthesis, so T1DM leads to increased level of KB = Ketoacidosis.

Question 22

Only place in body where ketone bodies are synthesized

Answer 22

Liver. Liver is required to supply both glucose and ketone bodies.

Question 23

Cellular location of FA synthesis v. degradation

Answer 23

Synthesize FA in cytoplasm and degrade (by beta-oxidation) in the mitochondria. This makes sense b/c degradation generates Acetyl-coA, which can go right into the TCA cycle in the mito

Question 24

Basic cause of NAFLD (non-alcoholic fatty liver disease)

Answer 24

insulin resistance. When insulin resistant, adipose tissue is NOT responding to insulin, so there is continual hydrolysis and the FA pool keeps coming back to the liver. The increase in FA exceeds the liver’s capacity of VLDL synthesis, so get accumulation of fat droplets.

Question 25

What is the purpose of FA beta-oxidation?

Answer 25

to generate acetyl-coA for use in the TCA cycle

Question 26

Insulin signaling. Name (3) forms of storage it promotes and (2) catabolic processes it shuts down

Answer 26

Insulin is controlling hormone in Fed state. Promotes glucose utilization and nutrient storage in forms of glycogen, TAG, and protein. At same time, insulin signaling shuts down catabolic processes for glycogen and TAG breakdown (inhibits HSL)

Question 27

What does the citrate shuttle do? Why?

Answer 27

Transports acetyl-coA out of the mito into the cytosol. Why = FA biosynthesis. Acetyl-coA is made inside mito from pyruvate of glycolysis. But must be shuttled out into the cytoplasm for FA synthesis.

Question 28

How is FA synthesis directly related to carbohydrate (and protein) intake?

Answer 28

From fact that decarboxylation of pyruvate makes Acetyl-coA (in mito), and acetyl-coA is substrate for FA synthesis (in cytoplasm). Pyruvate levels maintained by glyolysis and amino acid metabolism activated by insulin in fed state. Thus, greater the carb (protein) intake, the more FA synthesized.

Question 29

Levels of which molecule control citrate movement to the cytoplasm from the mitochondria?

Answer 29

ATP. Increase in ATP leads to increased cytosolic citrate levels to be used for more FA synthesis.

Question 30

(2) enzymes of FA synthesis

Answer 30

``` ACC = acetyl-coA carboxylase (regulated step!) FAS = fatty acid synthase ```

Question 31

What is ACC and how is it regulated?

Answer 31

ACC = acetyl-coA carboxylase. It is the first step in FA synthesis. Regulated multiple ways: - Hormonal: Insulin stimulates ACC. Glucagon and Epi inhibit it. - Allosteric: citrate binding promotes ACC activity - Long-term diet-induced: chronic high calorie diet will increase transcription of ACC and vice versa.

Question 32

Name the (2) essential fatty acids. What makes them essential?

Answer 32

omega-3-linoleNic and omega-6-linoleic acid. Humans lack the desaturase enzymes that catalyze the reduction of the fatty acid chain within 6 carbons of the omega end. Since we can't synthesize omega-3 or -6, must get from diet. These 2 FA are required for precursors of Eicosanoid hormones.

Question 33

(4) stages and the major intermediates in cholesterol biosynthesis

Answer 33

1) Regulated step. HMG-CoA synthase converts Acetyl-coA into HMG-CoA. Then, HMG-CoA reductase (REGULATED STEP) converts HMG-CoA into Mevalonate. 2) Energy expended step. 3 ATP required to turn mevalonate into C5 isoprene building blocks 3) Relevant lipid intermediates step. Condensing the C5 isoprenes make Geranyl and Farnesyl pyrophosphate. More condensation makes Squalene. 4) Final enzyme/SLOS step. Squalene into Lanosterol. Then, 7-dehydrocholesterol reductase (encoded by DHCR7 gene) turns lanosterol into cholesterol.

Question 34

Name (2) biologically relevant lipid intermediates in the cholesterol synthesis pathway and how they relate to Ras

Answer 34

Farnesyl and Geranyl pyrophosphate. Both serve as lipid anchors for membrane proteins ("protein prenylation"). Ras = protein oncogene that is prenylated and attached to cell membrane. Since Ras is overactivated in a lot of cancers, there are clinical trials trying to inhibit the enzymes that attach farnesyl or geranyl (lipid anchors) to the membrane protein (Ras)

Question 35

What is major (non-transcriptional) regulation of HMG-CoA reductase?

Answer 35

Intracellular cholesterol levels through SREBP-2 Low cholesterol = high expression of HMG-CoA reduct High cholesterol = low expression of HMG-CoA reduct

Question 36

What does SREBP-2 do? What 2 genes it is associated with?

Answer 36

SREBP-2 is an integral membrane protein in the ER that works as a transcription factor for (2) genes: HMG-CoA reductase and LDL receptor. When cholesterol levels are low, it moves to the nucleus and promotes transcription of the 2 genes = increased cholesterol synthesis. High cholesterol keeps SREBP in the ER so that no transcription occurs.

Question 37

How do glucagon and insulin (post-transcriptionally) regulate HMG-CoA reductase activity?

Answer 37

Phosphorylation of HMG-CoA reductase INACTIVATES it: - Glucagon phosphorylates and inactivates it (b/c cells are in catabolic state to meet energy demands, so cholesterol synthesis is suppressed.) - Insulin phosphorylates and ACTIVATES it!

Question 38

Overall effect of statin drugs on HMG-CoA reductase

Answer 38

INHIBIT HMG-CoA reductase by acting as competitive inhibitors and binding to it to halt its activity

Question 39

Outline the (4) steps of LDL receptor-mediated endocytosis

Answer 39

1) Binding: LDL binds to receptor on the plasma membrane 2) Internalization: complex of LDL + its receptor are internalized into the lysosome where LDL then dissociates from the receptor 3) Hydrolysis: LDL degraded by lysosome into cholesterol esters (CE). Then CE hydrolyzed to free cholesterol 4) Delivery: cholesterol delivered to ER w/in the cell and LDL receptors RECYCLED back to plasma membrane to take up more LDL

Question 40

(3) regulatory actions that increased intracellular cholesterol has inside a cell after LDL-receptor mediated endocytosis

Answer 40

- decreased HMG-CoA reductase activity; - INCREASED ACAT activity (which catalyzes formation of cholesterol esters); and - decreased LDL receptors

Question 41

How do bile acid resins, such as Cholestyramine, lower LDL-cholesterol?

Answer 41

cholestyramine binds bile acids in the intestine and increases the amount of bile acids excreted. This leads to increased cholesterol metabolism into bile acids, which decreases hepatic cholesterol levels.

Question 42

How does Ezetimibe (Zetia) lower LDL-cholesterol?

Answer 42

Ezetimibe targets the uptake and absorption of cholesterol in the enterocytes by binding to NPC1L1 transporter. NPC1L1 = Niemann-Pick C1-Like 1. Is a cholesterol transporter on brush border of enterocytes

Question 43

What is PCSK9? What would inhibiting it do to LDL-cholesterol levels?

Answer 43

PCSK9 = protein that binds to the LDL-receptor and takes it to the lysosome for degradation rather than being recycled back to the membrane. So presence of PCSK9 blocks LDL-receptor recycling. Result = decreased receptors at plasma membrane and less ability to take up circulating LDL. Tx of statin + PCSK9 inhibitor will increase LDL-receptor recycling and increase uptake of circulating lipoprotein.

Question 44

What is the genetic basis and inheritance pattern for Type IIa Familial Hypercholesterolemia (FH)? What is the classic lipid profile of FH?

Answer 44

FH is autosomal DOMINANT genetic disorder where you inherit mutations in the LDL receptor. Classic lipid profile = high total cholesterol and LDL-cholesterol, but normal TAG and HDL levels.

Question 45

Describe the role of foam cell formation in atherosclerosis.

Answer 45

Consequence of chronically elevated LDL in circulation can be developing foam cells, which are macrophages loaded up w/ LDL-cholesterol. Presence of foam cells can be an initiating event in atherosclerotic plaque development.

Question 46

List the (2) major primary bile acids. What is the distinguishing difference between primary and secondary bile acid structure.

Answer 46

(2) primary BA = chenodexoycholic acid + cholic acid. These two can be metabolized by gut bacteria in intestines into secondary bile acids. Secondary BA can be distinguished from primary by ABSENCE of the C7 hydroxyl group

Question 47

Importance of conjugation of bile acids for function

Answer 47

Bile acids/salts function to emulsify dietary lipids. The acid form (COO-H+) has low solubility in intestinal lumen, leading to precipitation. However, conjugating BA into bile salts (C=O + neg-charged amino acid) makes the side chain neg-charged. This increases its solubility and, thus, its ability to emulsify lipids

Question 48

Importance of enterohepatic circulation to bile acids. What is the effect of bile acid resins on this pathway?

Answer 48

through the enterohepatic circulation, can get cycling of bile acids from the intestine to the liver several times a day. Bile acid resins bind to the BA in the intestine, which decreases amount of BA recycled back to the liver, thus increasing amount of excreted BA.

Question 49

What is CYP7A and what is the mechanism of bile acid regulation of CYP7A expression? Effect of bile acid resins?

Answer 49

CYP7A (7-alpha-hydroxylase) is the 1st enzymatic rxn in converting cholesterol into primary bile acids. It hydroxylates the C7 of cholesterol. Increased levels of BA suppress transcription of the CYP7A gene by negative feedback. BA resins decrease amount of BA being returned to the liver, which increases CYP7A expression leading to increased BA synthesis. Effect = increased clearance of cholesterol in circulation.

Question 50

Name the only C18 steroid and a distinguishing feature of it? How does this help you remember its enzyme?

Answer 50

Estradiol. Has an aromatic A ring. So Aromatase is the enzyme that produces estradiol.

Question 51

What are the C19 steroids? Name the (2) C17 ketosteroids part of this group.

Answer 51

C19 = androgens C17 keto steroids = Androstenedione and DHEA (Dihydroepiandrosterone). They both have a keto grp at C17 and are both ADRENAL steroids.

Question 52

Name the C21 steroids

Answer 52

glucocorticoids (Cortisol) and mineralcorticoids (Aldosterone). "Only adrenal steroids have 21 carbons." So if you see an enzyme like P450c21, you know its working on an adrenal steroid.

Question 53

Name the major steroids produced by the the Leydig cells, theca cells, and granulosa cells

Answer 53

- Leydig = testosterone - Theca = DHEA and androstenedione. Androstenedione then diffuses into granulosa cells where it's converted into estrone and estradiol by aromatase and 17-beta-HSD. - Granulosa = estrone and estradiol

Question 54

What do the (4) steroid nuclear receptors (MR, GR, ER, and AR) function as?

Answer 54

transcription factors. When their steroid ligands bind, the NR bind to promoter regions of target genes and stimulate transcription, which make changes w/in the cell/tissue, such as sexual maturation, reproduction, salt balance, etc.

Question 55

What (2) rxns each to Aromatase and 17-beta-HSD catalyze?

Answer 55

aromatase: androstenedione into estrone and testosterone into estradiol 17-beta-HSD: androstenedione into testosterone and estrone into estradiol

Question 56

Major steroids produced in the adrenocortical zones (name 2 in each of 3 layers)

Answer 56

from outer to inner: glomerulosa = Aldosterone and DOC (mineralcorticoids) fasiculata = Cortisol and 11-DOC (glucocorticoids) reticularis = C17 keto steroids (DHEA and Androstenedione)

Question 57

Elevated levels of C17 keto steroids in the urine is diagnostic for what?

Answer 57

excess adrenal androgen production

Question 58

Presence of ___ enzyme + absence of ____ enzyme = production of Aldosterone in the zona glomerulosa

Answer 58

Presence of Aldosynthase + absence of P450c17. Aldosynthase = ONLY in the ZG and converts corticosterone to aldosterone. P450c17 is in ZF and ZR and converts progesterone to 17-OHProg and then 17-OHProg to Androstenedione.

Question 59

Pathway of aldosterone production

Answer 59

Cholesterol > Pregnenolone > Progesterone > DOC > Corticosterone > Aldosterone

Question 60

Signaling pathways activated by LH v. FSH

Answer 60

LH stimualtes C19 androgen production (DHEA and androstenedione) in ovarian theca cells and testicular Leydig cells FSH targets ovarian granulosa cells to stimulate production of estrogen

Question 61

Signaling pathway activated by Angiotensin II

Answer 61

The angiotensin receptor is a G-protein coupled receptor that activates PLC (phospholipase C). PLC hydrolyzes PI into DAG + IP3. IP3 releases Ca from intracellular stores. Increased Ca signaling = increased transcription of steroid hormone synthesis enzymes, such as StAR and P450scc. Overall = increased steroid hormone output!

Question 62

What rxns do P450scc and 3-beta-HSD catalyze? What are the precursors for the 3 major adrenal steroids produced in each zone?

Answer 62

P450scc converts cholesterol into pregnenolone. Then HSD3B turns preg into progesterone. - Pregnenolone = androgen precursor - Progesterone = aldosterone and cortisol precursor

Question 63

Steroid signaling pathway activated by K+

Answer 63

K+ activates adrenal aldosterone synthesis. B/c K+ activates voltage-gated Ca channels on adrenal GLOMERULOSA cells. Increased Ca signaling = increased transcription of aldosterone synthesis enzymes. Result = increased aldosterone synthesis

Question 64

General mechanism for acute v. chronic regulation of steroid hormone biosynthesis

Answer 64

Are the 2 responses that happen when the peptide hormones ACTH, LH and FSH bind to their GPC-receptors and activate cAMP-PKA signaling. 1) acute = cholesterol delivered to the mito. c-AMP-PKA activates cholesterol ester hydrolase, which releases free cholesterol from CE stored in lipid droplets. 2) chronic = increased gene expression of the P450 enzymes. In response to ACTH, LH, or FSH, transcription factors bind to promoter regions of StAR and other CYPs to increase transcription/expression of enzymes.

Question 65

How can adipose tissue contribute to circulating sex hormone levels?

Answer 65

Adipose can convert C17 keto steroids to more potent sex hormones (estrogens and testosterone) due to having (2) enzymes: aromatase and 17-beta-HSD. - aromatase (down) converts androstenedione to estrone and testosterone to estradiol. - HSD17B (across) converts androstenedione to testosterone and estrone into estradiol.

Question 66

TAGs carried by chylomicrons v. VLDL

Answer 66

chylomicrons carry dietary TAGs, whereas VLDL carries endogenous (newly synthesized) TAGs

Question 67

List the 4 classes of lipoproteins with the origin of synthesis and lipid composition of each

Answer 67

- Chylomicrons (intestine): highest TAG and lowest cholesterol - VLDL (liver): high TAG, low cholesterol, and more protein/phospholipid content than chylomicrons - LDL (generated from depletion of TAG from VLDL): highest cholesterol/CE with low TAG - HDL (liver AND intestine): lowest TAG and high cholesterol

Question 68

List the functions of each of the 4 lipoprotein classes

Answer 68

- Chylomicrons: delivery dietary TAG to peripheral tissues - VLDL: deliver de novo TAG to peripheral tissues ("endogenous TAG transport") - LDL: deliver cholesterol to peripheral tissues - HDL: deliver cholesterol to the liver for elimination ("reverse cholesterol transport")

Question 69

What are the major structural apolipoproteins for chylomicrons v. VLDL? Which (2) additional apolipoproteins do both acquire after encountering circulating HDL?

Answer 69

Chylomicrons = ApoB-48 VLDL = ApoB-100 HDL provides ApoC-II and ApoE

Question 70

How is it that HDL plays an important role in chylomicron and VLDL synthesis and metabolism? [Hint: two apolipoproteins]

Answer 70

Both chylomicrons and VLDL are secreted into circulation before gaining all their functional apolipoproteins. Circulating HDL gives them both ApoC-II and ApoE. ApoC-II = cofactor for LPL, activating LPL activity. ApoE = endocytosis and clearance by the ApoE receptor of the liver.

Question 71

Function of lipoprotein lipase (LPL)

Answer 71

LPL hydrolyzes TAGs in chylomicrons and VLDL to FFA and glycerol. FFA released by LPL are taken up by adipose and resynthesized into TAGs for storage and by muscle, which oxidizes FFA for energy.

Question 72

Where is LPL located? Associated with what molecule? Why is this location important?

Answer 72

LPL is an extracellular enzyme attached to capillary walls via Heparin Sulfate, a lipid anchor. This location gives LPL access to circulating lipoproteins and ApoC-II, which is a cofactor for LPL, activating its activity.

Question 73

How are chylomicrons released into circulation (compared w/ VLDL)?

Answer 73

- Chylomicrons are secreted into intestinal lymphatic vessels and emptied into circulation via the thoracic duct. - VLDL is secreted directly into systemic circulation.

Question 74

What distinguishes LDL from other circulating lipoproteins?

Answer 74

LDL has only ApoB-100 associated with it

Question 75

What is IDL and which apolipoproteins are associated with it? What are (2) potential paths for IDL?

Answer 75

IDL = intermediate density lipoprotein. It's the VLDL remnant after the TAG content has been depleted and the ApoC-II recycled back to HDL. Thus, IDL has the Apo-E and ApoB-100 left from VLDL. -IDL can be cleared from circ by the liver through ApoE receptor-mediated endocytosis OR hepatic lipase in liver can do further depletion of TAG to make LDL

Question 76

Which enzymes create IDL and LDL?

Answer 76

``` LPL (lipoprotein lipase) hydrolyzes the TAG of VLDL to make IDL Hepatic Lipase (HL) does continual hydrolysis of the TAG in IDL to make LDL ```

Question 77

Which apolipoprotein binds the LDL receptor?

Answer 77

ApoB-100

Question 78

(2) reasons ApoA1 is important

Answer 78

it helps facilitate cholesterol transfer to the HDL particle AND is an activator of PCAT activity

Question 79

(3) apolipoproteins associated w/ HDL and their function

Answer 79

- ApoA-1 = (2) jobs: binds w/ membrane ABC transporters to move cholesterol from plasma membranes to the HDL AND activates PCAT for conversion of free cholest to CE. - Apo-CII: activates LPL activity - Apo-E: binds to Apo-E receptor on liver for receptor-mediated endocytosis

Question 80

HDL to HDL3 to HDL2

Answer 80

HDL made in liver and intestine and is devoid of lipid. The ApoA-1 on HDL helps HDL collect cholesterol from cells and activates PCAT conversion of free cholest to CE. - Once HDL accumulates CE = HDL3. - And as even more CE accumulates, the larger particle = HDL2. HDL2 is the major form taken up by the liver's SR-B1 receptors

Question 81

What is CETP and why is it needed?

Answer 81

CETP = cholesterol ester transport protein. CETP moves CE out of HDL into VLDL in exchange for phospholipids. Purpose is to maintain function of PCAT. Accumulated CE will feedback inhibit PCAT function so that HDL would not take up anymore cholesterol.

Question 82

What is the SR-BI? What is the purpose of high expression in both the liver and steroidigenic tissues?

Answer 82

the SR-BI (scavenger receptor, type I) mediates uptake of HDL cholesterol. - High expression of this receptor in the liver promotes reverse cholesterol transport - high expression in steroidigenic tissues supports HDL as major supplier of cholesterol for steroid hormone synthesis

Question 83

LPL regulation: Km (high/low) for ApoC-II binding of adipose LPL v. cardiac muscle LPL

Answer 83

-Adipose LPL has high Km -Cardiac muscle LPL has a low Km [High Km = low affinity of enzyme for its substrates.] Thus, this diff sets preference for muscle utilization of FFA when lipoprotein levels are low. But when levels are high, such as in fed state, binding to adipose LPL occurs and the TAG is stored for later use.

Question 84

Hormonal regulation of LPL - insulin v. glucagon

Answer 84

- Insulin stimulates synthesis and expression of LPL on the cell surface. Makes sense b/c in fed state chylomicron and VLDL levels are high, so increase in LPL facilitates uptake and storage of FFA/TAG - Glucagon decreases LPL activity. Don't need LPL when VLDL/chylo levels are low

Question 85

How do Fibrates (e.g. Clofibrate) regulate LPL activity?

Answer 85

Fibrates increase LPL expression. They are ligands for PPAR-alpha, which binds to the promoter of the LPL gene and increases transcription

Question 86

Name, disorder, and classic lipid profile of Type 1 hyperlipidemia

Answer 86

Type 1 = Hyperchylomicronemia (elevated plasma chylomicrons). Is a primary disorder w/ genetic mutation in either LPL or Apo-CII (it's cofactor). Lipid profile = floating milky layer (of TAG) in blood sample and elevated TAG levels that resolve by a fat-free diet.

Question 87

Name, disorder, and classic lipid profile of Type IIa hyperlipidemia

Answer 87

Type IIa = FH (familial hypercholesterolemia). Primary disorder w/ mutation in LDL receptor. Lipid profile = high total cholesterol and LDL. But normal TAG and HDL.

Question 88

Name, disorder, and classic lipid profile of Type IIb hyperlipidemia

Answer 88

Type IIb = Familial combined hyperlipidemia. Has both a primary disorder (that is complex) and secondary disorder, such as insulin resistance, obesity, or diabetes. Lipid profile = high cholesterol and moderate-to-high TAG with LOW HDL.

Question 89

Name, disorder, and classic lipid profile of Type III hyperlipidemia. What's the only way to distinguish between Type IIb and Type III?

Answer 89

Type III = Familial Dysbetalipoproteinemia. Primary disorder is inheritance of a mutant ApoE that has reduced binding affinity for the ApoE remnant receptor. So these pts cannot clear chylomicron remnants or IDL as well. Lipid profile: since remnants carry both TAG and cholesterol, both are elevated. Genetic screen for ApoE alleles = only way to distinguish between type IIb and type III

Question 90

Name, disorder, and classic lipid profile of Type IV hyperlipidemia

Answer 90

Type IV = Hypertriglyceridemia. Not due to primary genetic disorder, but to secondary to obesity, insulin resistance, T2DM, or alcoholism. Lipid profile = dx of metabolic disorder + elevated TAG + marginally elevated cholesterol

Question 91

What is the biochemical basis for alcoholism contributing to Type IV hyperlipidemia?

Answer 91

Due to the liver enzymes (ALD + ALDH) that oxidize ethanol. Both are NAD+-dependent and make high levels of NADH. High NADH inhibits FA-beta-oxidation and promotes TAG synthesis. Therefore, VLDL synthesis increases.

Question 92

Hormone profile indicating a direct adrenal problem (Addison's disease)

Answer 92

low cortisol and low aldosterone with | high CRH and high ACTH

Question 93

Levels of which hormones indicate a primary adrenal insufficiency v. secondary (pituitary problem) or tertiary (hypothamic problem)?

Answer 93

decreased levels of BOTH cortisol and aldosterone point to a primary adrenal insufficiency. If secondary or tertiary and the CRH-ACTH signaling is disrupted, that would only decrease cortisol, but have no effect on aldosterone. So: - secondary = low cortisol due to low ACTH, but high CRH due to low cortisol - tertiary = all three low (CRH, ACTH, and cortisol)

Question 94

Which signaling pathway regulates aldosterone levels?

Answer 94

Angiotensin II and K+ levels

Question 95

Common pathophysiology for CAH

Answer 95

low cortisol and high ACTH

Question 96

Recognize the phenotype of a patient with glucocorticoid excess

Answer 96

i. e. Cushing's Syndrome/Disease. (3) features: - Central obesity: fat around abd, "buffalo hump," and moon face - Protein wasting: thin extremities due to muscle wasting b/c glucocorticoids have catabolic effects on muscle - Hypertension

Question 97

Differences in serum hormone profiles of Addison's disease, Cushing's syndrome, and Cushing disease.

Answer 97

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Question 98

Describe the different forms of 21-alpha-hydroxylase deficiency. Due to mutation in what gene?

Answer 98

Due to mutations in the CYP21 gene. (3) types: - Classical salt-wasting: get loss of cortisol and aldosterone synthesis due to inactivating mutation of CYP21. Get elevated adrenal androgens and masculinization/ambig genitalia in F - Classical simple virilization: no loss of aldosterone production, but get elevated androgens = early virilization in M and ambig genitalia in F. - Non-classical C21 deficiency: most common. Aldosterone production unaffected and no genital ambiguity in F.

Question 99

How can the excess androgens produced in 21-alpha-hydroxylase deficiency lead to azoospermia?

Answer 99

Increased adrenal androgens (Androstenedione) can be converted into testosterone in adipose tissue. Excess testosterone production will negatively feedback inhibit FSH and LH, which will lead to decreased testosterone in the testis, negatively impacting sperm production.

Question 100

Which steroid pathways are affected by 17-alpha-hydroxylase deficiencies?

Answer 100

BOTH the adrenal and gonadal steroidogenic pathways. 17-alpha-hydroxylase converts Preg into DHEA and Prog into androstenedione (A4). - In adrenals, high Progesterone lead to accumulation of mineralcorticoid, DOC. Kidney responds to high DOC with increased Na+-retention, leading to HTN. - in gonads, inability to convert preg/prog into DHEA/A4, leads to decreased testosterone or estrogen production. Result = feminization of males due to loss of T and DHT.