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CardioPulmonary Vascular Disease > Cholesterol Synthesis > Flashcards

Cholesterol Synthesis Flashcards

1
Q

Endogenous cholesterol is produced primarily in which organ?

A

liver

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2
Q

Cholesterol serve as precursors to which bio macromolecules?

A

Vitamin D, Sterol hormones, Bile acids

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3
Q

What enzyme catalyzes the rate limiting step of bile acid synthesis?

A

7-hydroxylase

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4
Q

How can a vegetable rich diet manage high cholesterol?

A

plant sterols in the diet inhibit the absorption of cholesterol in the diet

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5
Q

What are 3 ways in which serum cholesterol levels can be lowered?

A

Decreased dietary intake of cholesterol; decrease cholesterol synthesis; increase excretion of bile acids

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6
Q

What type of cholesterol comes from extrahepatic tissues

A

HDL

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7
Q

In what form is cholesterol distributed throughout the blood stream?

A

VLDL

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8
Q

What extrahepatic organs can also synthesize cholesterol?

A

adrenals, gonads, intestine, placenta

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9
Q

cholesterol is synthesized in which part of the cell?

A

cytoplasm

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10
Q

Describe Stage 1 of cholesterol biosynthesis?

A

Excess acetylCoA from mitochondrial matrix gets converted to mevalonate by HMG CoA reductase

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11
Q

For stage 1 of cholesterol synthesis, what is the role of thiolase?

A

converts acetylCoA to Acetoacetyl CoA

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12
Q

What is the rate-limiting step for cholesterol synthesis?

A

HMG CoA reductase; conversion of Acetoacetyl CoA to Mevalonate; requires 2X NADPH; irreversible

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13
Q

what enzyme is involved in the esterification of cholesterol?

A

ACAT or LCAT (HDL)

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14
Q

Describe the SREBP/SCAP regulation of cholesterol synthesis when serum levels of cholesterol are low.

A

SCAP-SREBP complex is transported to golgi apparatus; Once in the Golgi, SCAP activates proteases to cleave SREBP to release the SREBP DNA-binding domain; this domain then translocates to the nucleus to bind to SRE which is the gene that encodes for the HMG CoA reductase

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15
Q

Describe the SREBP/SCAP regulation of cholesterol synthesis when serum levels of cholesterol are high.

A

cholesterol binds to SCAP and inactivates it

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16
Q

How is cholesterol synthesis regulated in post-transcriptional pathways when serum levels of cholesterol are high

A

proteolysis of HMG CaA reductase; degradation of mRNA carrying genetic code for HMG CoA reductase

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17
Q

how do glucagon & insulin affect cholesterol synthesis respectively?

A

Glucagon increases cholesterol synthesis by activating AMPK (phosphorylation); Insulin decreases cholesterol synthesis by activating phosphatase (dephosphorylation)

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18
Q

How do high levels of AMP affect cholesterol synthesis?

A

activates AMPK and increases cholesterol synthesis (phosphorylation)

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19
Q

what determines the density of lipoproteins?

A

amount of triglycerides; higher triglyceride to protein ratio is associated with Lower density

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20
Q

What type of lipoproteins transport dietary lipids from intestine to the liver & tissues?

A

Chylomicrons (least dense; biggest diameter)

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21
Q

What lipoproteins transport endogenous lipids from the liver?

A

VLDL

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22
Q

What lipoproteins transport cholesterol from liver to tissues with high cholesterol demands (adrenal, sex glands)?

A

LDL

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23
Q

What Lipoproteins transport cholesterol from tissue back to the liver?

A

HDL

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24
Q

Where are chylomicrons synthesized?

A

intestinal epithelial cells

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25
Q

What is the Role of ApoB48?

A

assembly and secretion of chylomicrons in small intestine assisted by MTP

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26
Q

Chylomicrons are secreted from the intestines as lymph and enter the blood stream through which lymphatic outlet?

A

thoracic duct

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27
Q

ApoB48 is produced via RNA editing of which gene?

A

ApoB-100; C edited to U creates a stop codon; basically a shorten transcript compared to the traditional Apo100 which is 52 times the size of Apo48

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28
Q

What enzyme is responsible to the hydrolyzation of TGs in chylomicrons and where are these enzymes located?

A

LPL; located in BM of capillary endothelium

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29
Q

LPL is activated by which enzyme & what peptide hormone upregulates its synthesis?

A

LPL is activated by ApoCII and upregulated by insulin

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30
Q

Chylomicrons remnants are taken up by which organ and what is the ligand for the hepatocytes to take up these remnants?

A

liver; ApoE on remnants bind to ApoE receptor in hepatocytes

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31
Q

chylomicron remnants ……… in size & …….. in density as more content is taken up by tissues?

A

decreases; increases

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32
Q

What is the main metabolic source of VLDLs?

A

excess carbohydrates

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33
Q

What is the apoprotein for VLDLs & LDL?

A

ApoB-100

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34
Q

By then end of a chylomicron’s journey, what type of micelle does it become?

A

HDL: low levels of TGs & fatty acids & higher concentration of proteins

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35
Q

LDL is rich in what?

A

cholesterol

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36
Q

How can excess LDL cause atherosclerosis?

A

LDLs are oxidized by macrophages which forms foam cells that can build up to plaques

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37
Q

Esterification prevents cholesterol from doing what?

A

moving out of the cytoplasmic membrane

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38
Q

ApoA is associated with what apoprotein?

A

HDL

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39
Q

What is the process by which cells get rid of cholesterol?

A

Reverse Cholesterol Transport

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40
Q

How is cholesterol transported out of the cell?

A

ABC1 ATPase

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41
Q

What two proteins are required for HDL to extract cholesterol from extrahepatic tissues?

A

LCAT (activated by Apo A1) traps cholesterol in the micelle & CETP (exchanges cholesterol ester from HDL to VLDL)

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42
Q

HDLs bind to which receptors on hepatocytes?

A

SR-B1

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43
Q

Describe the pathogenesis of Hyperlipoproteinemia Type I?

A

LPL deficiency; insufficient digestion of Triglycerides will decrease the body’s ability to break down VLDL & chylomicrons leading to high levels of these and low levels of HDL & LDL

44
Q

What are the multiple pathogenesis for Type IIa hyperliporoteinemia?

A

Defective LDL Receptor, ApoB100, PCSK9

45
Q

What is the role of PCSK9 in lipid metobolism?

A

binds to LDL receptors and targets them for lysosomal degradation leading to increased serum levels of LDL

46
Q

Describe the pathogenesis of Hyperlipoproteinemia Type III

A

Defective ApoE

47
Q

What is the pathogenesis of Type IV hyperlipoproteinemia?

A

overproduction of VLDL due to glucose intolerance

48
Q

What is the pathogenesis of Tangier disease?

A

hypolipoproteinemia caused by defects in ABC1 genes

49
Q

Describe the pathogenesis of Abetalipoproteinemia.

A

hypolipoproteinemia; MTP gene mutations

50
Q

Describe the pathogenesis of hypoalphalipoproteinemia.

A

hypolipoproteinemia; accelerated breakdown of ApoA-1 & ApoA-II

51
Q

Wolman’s disease is associated w/ defects in what protein?

A

lysosomal acid lipases

52
Q

LCAT deficiency leads to what?

A

low HDL levels and cholesterol accumulation in tissues

53
Q

Why is Type I Hyperlipoproteinemia not associated with increased risk of CAD?

A

A defect of LPL will reduce bioavailability of cholesterol in the tissues since less of it is being transported; therefore we would expect to see increased levels of chylomicron, VLDL and decreased levels of LDL & HDL

54
Q

What would be the physiological consequence of a defective PCSK9 based on your knowledge of what this protein does?

A

PCK9 defect would increases serum levels of LDL, cholesterol and therefore increase risk of CAD

55
Q

what would be the physiological consequences of na defective LDL receptor?

A

Resistant to breakdown by protease; LDL will accumulate leading to hyperlipoproteinemia

56
Q

What would be the physiological consequence of a defective ApoB100?

A

increased serum levels of VLDL & LDL

57
Q

Based on your knowledge of role ApoE plays in cholesterol metabolism, what would you expect to be the physiological consequences of a defect in this protein to be?

A

ApoE is required for chylomicron uptake into hepatic tissue so it would make sense for serum levels of chylomicrons to be elevated; extrahepatic endogenous VLDL will also be elevated since they cannot be taken up by the liver; xanthomas

58
Q

Overproduction of VLDL is typically associated with what medical conditions?

A

glucose intolerance assoc. w/ DM, CHD, obesity

59
Q

What would we expect to be elevated in serum of pts. with Type IV hyperlipoproteinemia?

A

TGs & VLDL

60
Q

Based on your knowledge of the role ABC ATPases play in cholesterol metabolism, what would you expect the physiological consequences to be if these ATPases were defective?

A

Lipids & cholesterol will not be able to be transported out of the cell which will decrease serum levels of HDL and cause hypolipoproteinemia

61
Q

Based on your knowledge of the role MTP plays in cholesterol metabolism, what would you expect the physiological consequences to be if this protein was mutated?

A

decreased assembly of Chylomicrons will decrease serum levels of all micelles leading to hypolipoproteinemia

62
Q

Based on your knowledge of the role ApoA proteins play in cholesterol & lipid metabolism, what would you predict to be the physiological consequences if degradation of these proteins was increased?

A

ApoA proteins are assoc. w/ HDL so we would expect serum levels of HDL to be lowered; this will cause hypolipoproteinemia b/c HDL cannot be extracted from extrahepatic tissues

63
Q

What is the physiological consequence of LCAT deficiency?

A

LCAT is one of the two required proteins for extrahepatic extraction in the reverse cholesterol process; therefore HDL will be trapped in extrahepatic tissue thus lowering serum HDL levels

64
Q

What is the pathogenesis of fatty liver disease?

A

decreased hepatic synthesis of apolipoproteins resulting in decreased production of VLDL which leads to TG accumulation in the liver

65
Q

What is the precursor for bile salts?

A

cholesterol

66
Q

What is the main route of cholesterol elimination from the body?

A

feces

67
Q

in what organ are bile acids stored?

A

gallbladder

68
Q

Bile salts have poor solubility; how does the body compensate for this?

A

hydroxylation and carboxylation of bile salts increases their solubility

69
Q

What are the 2 main primary bile salts and what makes them primary bile salts?

A

cholic acid & chenodeoxycholic acid; primary b/c they are produced in the liver

70
Q

what are the 2 main secondary bile salts and what makes them secondary bile salts?

A

deoxycholic acid & lithocholic acid; secondary b/t they are formed from primary bile acids by bacterial enzymes in the small intestine

71
Q

why are secondary bile salts more likely to be excreted than primary bile salts?

A

lost of hydroxyl group decreases solubility and therefore decreases reabsorption

72
Q

Describe the process of Bile Salt conjugation?

A

addition of an amino acid to the carbon 24 carboxylate; Usually glycine or taurine

73
Q

conjugated bile salts have a lower pKa than physiological pH; what form will therefore predominate in small intestinal pH (6)?

A

higher percentage of the ionized form of conjugated bile acid

74
Q

The majority of Bile Acid reabsorption takes place in what part of the colon?

A

Ileum

75
Q

What is another name for Type I hyperlipoproteinemia?

A

familial LPL deficiency

76
Q

what is another name for Type IIa hyperlipoproteinemia?

A

familial hypercholesterolemia

77
Q

what is another name for Type IV hyperlipoproteinemia?

A

familial hypertriacylglycerolemia

78
Q

List the components of Metabolic Syndrome.

A

large waistline; high serum levels of TGs & LDL; low serum levels of HDL; HTN; Glucose intolerance

79
Q

what is the definition of dyslipidemia?

A

generic umbrella term for abnormal serum levels of lipids

80
Q

severe hypertriglyceridemia can lead to what?

A

acute pancreatitis

81
Q

what are the parameters for diagnosis of metabolic syndrome?

A

3 of the following:
blood glucose > 100 mg/dL
BP of at least 130/85
TG > 150 mg/dL
HDL < 40 mg/dL for men; <50 mg/dL for women
waist circumference > 102 cm (40 in.) in men; > 88 cm (35 in.) in women

82
Q

what is a clinical hallmark of familial combined hyperlipidemia?

A

disproportionately elevated levels of apoB

83
Q

what is a major clinical hallmark for dyslipidemia induced by defective LDL receptor?

A

xanthomas; arcus corneae

84
Q

Of all the drugs you have learned up to this point, composite a list of drugs that can potentially increase serum levels of cholesterol.

A

Thiazides; BBs, antiretroviral agents; estrogen supplements; glucocorticoids, cyclosporine, tacromilus

85
Q

What are other systemic diseases that can cause dyslipidemia besides primary dyslipidemia & cholestatic liver disease?

A

CKD; Nephrotic syndrome; hypothyroidism; cushing disease

86
Q

what can cause excessive hepatic production of VLDL?

A

high carbohydrate diet; obesity; insulin resistance; nephrotic syndrome; cushing’s syndrome; alcohol abuse disorder

87
Q

What is the mechanism of alcohol-induced dyslipidemia?

A

ethanol inhibits hepatic oxidation of free fatty acids leading to excess production of VLDL; this promotes TG synthesis and VLDL secretion which will subsequently raise plasma levels of HDL

88
Q

What are common causes of decreased lipolysis of TGs and lab findings?

A

obesity; insulin resistance; LPL defect; lab findings: elevated TG, Low HDL with no elevation of LDL or apoB

89
Q

Impaired hepatic uptake of lipoproteins containing ApoB would be indicative of what lab findings and what are common causes?

A

elevated LDL & TG; common causes include hypothyroidism & CKD

90
Q

what are common secondary causes of reduced HDL levels?

A

cigarette smoking, steroids, HIV, nephrotic syndrome

91
Q

hypercholesterolemia is assoc/ with what condition?

A

cholestasis

92
Q

BBs …… levels of HDL & ………. levels of VLDL.

A

reduce; elevate

93
Q

Thiazides ……. levels of LDL

A

elevate

94
Q

Estrogen …….. levels of HDL, ……… levels of VLDL & TG

A

elevate; elevate; elevate

95
Q

What are some of the neurological effects of extremely high triglyceride levels?

A

paresthesias, dyspnea, confusion

96
Q

Acute pancreatitis induced by hypertriglyceridemia can be indicated by what clinical symptoms?

A

eruptive xanthomas when TG > 1000 mg/dL; lipemia retinalis when TG > 2000 mg/dL

97
Q

high levels of LDL can present with what?

A

arcus corneae; tendinosus xanthomas; xanthelasma

98
Q

what tendons are typically affected by hypercholesterolemia?

A

extensor tendons of upper & lower extremities

99
Q

what does arcus corneae look like?

A

extra layer of sclerae in between rim of the cornea and the iris

100
Q

what does xanthelasmas look like?

A

yellow cholesterol plaques surrounding canthus of upper eyelid

101
Q

how can inflammation affect lab values of a lipid panel?

A

increase levels of TG and decrease levels of cholesterol

102
Q

what is the equation for calculating LDL?

A

LDL = TC -[HDL + (TG/5)]; note only valid when TG level < 400 mg/dL

103
Q

familial hypercholesterolemia is clinically diagnosed based on what lab findings?

A

elevated LDL in the absence of hypertriglyceridemia

104
Q

what supplements can be recommended for management of hypertriglyceridemia?

A

niacin, fibrates, omega-3 fatty acids

105
Q

heterozygous and homozygous familial hypercholesterolemia are clinically defined by what parameters?

A

hetero: LDL > 190 or > 160 for ped. pts.; homo: LDL > 500

CardioPulmonary Vascular Disease (7 decks)

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