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GI > Lipoproteins > Flashcards

Lipoproteins Flashcards

1
Q

Friedewald equation (mg/dl)

A

LDL = total cholesterol - HDL - (total triglycerides/5)

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2
Q

Most plasma cholesterol is in ______ form.

A

esterifeid.

Fatty acid attached at C3: makes structure more hydrophobic

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3
Q

How are cholesterol and its esters transported?

A

in association with a protein as a component of a lipoprotein particle

or

solubilized by phospholipids and bile salts in bile

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4
Q

What is a chylomicron?

A

lipoprotein particle derived from the intestine;

part of exogenous pathway of lipoprotein metapolism

NB: source of liver cholesterol is from diet (via chylomicron remnants)

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5
Q

What is the lipoprotein particle derived from the liver?

Which pathway of lipoprotein metabolism?

A
  • VLDL

- endogenous pathway

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6
Q

What is liver’s role with cholesterol?

A
  • central!
  • Sources: diet (chylomicron remnants); local synthesis; extrahepatic tissues (via HDL and LDL)

Liver export cholesterol:

1) in VDL
2) excretes it in bile
3) converts it to bile salts

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7
Q

Where does cholesterol synthesis take place?

A

cytosol of virtually all cell types

De novo: liver and intestine

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8
Q

Name the following key factor in cholesterol synthesis

-source for carbon atoms:

A

Acetyl-CoA

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9
Q

Name the following key factor in cholesterol synthesis:

-major co-factor

A

2 NADPH

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10
Q

Name the following key factor in cholesterol synthesis:

-catalyzing enzyme of the regulated step

A

HMG-CoA reductase

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11
Q

Name the following key factor in cholesterol synthesis:

-product of the committed step

A

Mevalonate (5 carbons)

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12
Q

Is ATP consumed in making mevalonate?

the committed step

A

Yes

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13
Q

What is the committed step (what to what, how)?

A

HMG-CoA –> Mevalonate

  • catalyzed by HMG-CoA Reductase
  • using 2 NADPH as a cofactor
  • consuming ATP
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14
Q

What does mevalonic acid give rise to?

A

a) squalene –> lanosterol –> cholesterol

b) terpenes (isopreniods/isoprenes): farnesyl pyrophosphate, dolichol, ubiquinones, geranylgeranyl pyrophosphate

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15
Q

Which products of mevalonic acid can be conjugated with proteins and then serve as lipid anchors?

A

farnesyl pyrophosphate

geranylgeranyl pyrophosphate

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16
Q

What is the role of dolichol pyrophosphate?

A

(dolichol is a product of mevalonic acid)

required for the dolichol pathway of N-linked posttranslational protein glycolsylation

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17
Q

What is the role of ubiquinones?

A

product of mevalonic acid

ubiquinones can be reduced to ubiquinols, which can donate electrons to ETC as part of oxphos

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18
Q

What are 2 enzymes required for esterification of cholesterol?

A

1) ACAT

2) LCAT

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19
Q

What is the purpose of esterification of cholesterol?

A

cholesterol esters are more hydrophobic than cholesterol, enabling them to be packaged, stored, and transported easily

(therefore cannot be incorporated into membranes or transported through them nakedly)

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20
Q

Where are cholesterol esters found?

A

hepatocytes and steroid cells
(stored in lipid droplets in cytosol)

NB: most ofter cells contain virtually no cholesterol esters

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21
Q

Where does ACAT work?

A

epithelial cells of small intestine and in liver

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22
Q

Where does LCAT work?

A

blood: LCAT bound to HDL
uses FA from phospholipid lecithin on peripheral cell to esterify cholesterol to cholesterol esters, which are stored in HDL

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23
Q

How does cholesterol act to control de novo cholesterol synthesis?

A

1) stimulates proteolysis of HMG CoA reductase (neg fb)

2) regulates expression of HMG-COA reductase gene by influencing RNA pol II’s rate of HMG-CoA reductase mRNA synthesis

24
Q

What is the effect of insulin on HMG-CoA reductase (HMGR)?

A

stimulates

indicating glucose abundant and therefore signal of growth and anabolism

25
Q

What is the effect of glucagon on HMG-CoA reductase?

A

inhibits

to preserve acetyl-CoA fot the TCA cycle

26
Q

What are the liver pools of cholesterol (and cholesterol-ester) in balance with?

A

cholesterol-ester pools in lipoproteins

which are in balance with deposits in peripheral tissues

27
Q

What is the effect of excess cholesterol on:

  • ACAT?
  • hepatocyte uptake of cholesterol?
  • levels of HMG-CoA?
A
  • ACAT: ACTIVATES
  • hepatocyte uptake of cholesterol: INHIBITS
  • levels of HMG-CoA: REDUCES (stimulates its degradation)
28
Q

What is the mechanism of short-term hormonal regulations?

Hint: HMG-CoA reductase (HMGR)

A

Phosphorylation of HMG-CoA reductase (HMGR) leads to its INACTIVATION

29
Q

What are statins? Consequences?

A

Structural analogues of HMGR that competitively inhibit HMGR activity

they reduce the de novo cholesterol synthesis, decreasing intrahepatic cholesterol and causing increased rate of LDL removal from circulation
with increased qty and activity of hepatic LDL receptors

30
Q

What is SLOS?

A

metabolic disoder caused by a mutation in the DHCR7 gene on chromosome 11

DHCR7 codes for enxyme involved in cholesterol production

31
Q

What are clinical features of SLOS?

A

microcephaly, ptosis, broad nasal bridge, upturned nose, micrognathia, cleft palate, short thumbs, polydactyly, syndactyly

32
Q

What are apolipoproteins?

A

lipid-binding proteins in the blood responsible for the transport of TAGs, PL, Cholesterol, and Cholesterol esters (CE)

33
Q

What is the relative size and density of chylomicrons?

A

lowest in density;
largest in size,
contain highest percentage of lipid
contain lowest percentage of protein

34
Q

What re the fxns of apolipoprotins?

A

provide recognition sites for cell-surface receptors

serve as activators or coenzymes for enzymes involved in lipoprotein metabolism

35
Q

What is the major source and fxn of chylomicrons?

A

intestine
transport dietary TAG
(major apolipoprotiens: B48, CII, CIII, E)

36
Q

What is the major source and fxn of VLDL?

A

Liver.
Transport endogenously synthesized TAG
(major apolipoprotiens: B100, CII, CIII, E)

37
Q

What is the major source and fxn of LDL?

A

formed in circulation by partial breakdown of IDL;
delivers cholesterol to peripheral tissues
((major apolipoprotiens: B100)

38
Q

What is the major source and fxn HDL?

A

Liver.
removes “used” cholesterol from tissues and takes it to liver
acts as reservior for apos, which can be donated or received from other lipoproteins)

(major apolipoprotiens: AI, and AII, CII, CIII, E)

39
Q

What are the 3 pathways for lipoprotein metabolism?

A

1) exogenous pathway –> diet (chylomicrons)
2) endogenous pathway –> de novo (VLDL, IDL, LDL)
3) reverse cholesterol transport pathway –> largely dealing with cholesterol (HDL)

40
Q

Explain the exogenous path

A

foods from animals only –> jejunum epithelial cells take up sterols (bind to NPC1L1) endocytosis –>intestine incorporates cholesterol and cholesterol esters into chylomicrons –> loss of associated TAGs –> cholesterol-rich chylomicron remnants enter the liver

41
Q

What is the role of HDL in the exogenous path?

A

Reservoir of apoproteins:

1) CII: lipoprotein lipase activator (essential cofactor)
2) CIII: inhibitor of lipoprotein lipase inhibitor (blocks the block so lets more LPL act)
3) E: remnant receptor binding (servs as ligand for receptor-mediated clearance of chylomicron from liver

42
Q

Lipoprotein Lipase

A

Extracellular protein on walls of blood capillaries, anchored to epithelium

Hydrolyze: TAG –> FFA + glycerol

Some FFA released to circulation, bound to albumin.
80% transported to tissue
20% to liver

cleaves FAs from TAGs in anhydrous core of lipoproteins –> diminishes TAG content by changing ratio of TAG to CE

43
Q

Hepatic Lipase

A
  • phospholipase and triglyceride hydrolase activity
  • synthesized on hepatocytes; present primarily on liver endothelial cells
  • hydrolyzes TAGs (and possibly excess surface phospholipids in final processing of chylomicron remnants
  • completes processing of IDL to LDL
  • participates in the conversion of HDL2 to HDL3 by removal of TAG and phospholipid from HDL2

*apo CII is not a co-factor (but it is in LPL)

44
Q

Which has the longer half-life: VLDL or chylomicrons?

A

VLDL (expressed in terms of hours, not fractions of hours)

45
Q

What are the apos on each:
VLDL
IDL
LDL

A

VLDL: E, C, B100
IDL: E, B100
LDL: B100

46
Q

Which has the longer half life? VLDL or HDL

A

HDL: measured in days

47
Q

What lipids are the majority observed in fasting blood?

A

VLDL and IDL

48
Q

What is the fxn and fate of LDL?

A

~2/3 taken up by liver via ApoB100 binding to the LDL receptor

~1/3 taken up by peripheral tissues (thus is a sig source of cholesterol for these peripheral tissues)

49
Q

What modulates the expression of LDL receptors in cells (hepatocytes and peripheral cells)?

A

concentration of cholesterol that SREB2 senses in the ER membrane

*PCSK9 prevents recycling of LDL receptors back to PM

50
Q

Where are SR-A receptors expressed and why?

A

scavenger receptor: macrophages and some endothelial cell types (e.g.: intestine, spleen)
receptor has lower affinity but broader specificity (can also recognize damaged receptors)

free cholesterol is released into cytosol

51
Q

What is reverse cholesterol transport?

A

from peripheral tissues to liver

performed by HDL

52
Q

What is CETP and it’s overall effect?

A

Cholesterol Ester Transfer Protein:

net mass transfer of:

1) cholesterol esters from HDL to VLDL
2) TAG from VLDL to HDL

53
Q

What are the clinical manifestations of hyperTAGmia?

A

-increased risk of CV disease, pancreatitis, xantomas

54
Q

What are the clinical manifestations of chylomirconemia?

A

-pathologic presence of chylomicrons after 12-14 hrs fasting

Clinical: eruptive xanthoma, lipemia retinalis, hepatosplenogmegaly, focal neurologic symptoms (irritability), recurrent epigastric pain, increased risk of pancreatitis

55
Q

What are distinguishing factors of familial chylomicronemia and primary mixed hyperlipidemia?

A

r(elative to each other)

primary mixed hyperlipidemia:

  • later onset (adulthood)
  • less severe fxnional deficiency
  • infrequent detection of gene mutation
  • higher prevalence
  • presence of secondary factors
  • greater elevation of total cholesterol

vs.

familial chylomicronemia:

  • onset in childhood
  • BIOCHEMICALLY PROVEN DEFICIENCY OF LIPOPROTEIN LIPASE, APO CII ACTIVITY, OR HOMOZYGOUS GENE MUTATIONS
  • lower pop prevalence
56
Q

What is familiar hyperchylomicronemia:

Type 1?

A

Type 1: LPL deficiency or C-II deficiency

57
Q

What is familiar dysbetalipoproteinemia:

hyperlipoproteinemia Type 3?

A

deficiency for Apo-E

  • serum [IDL] are increased, resulting in TAG (250-400mg/dl), due to overproduction or underutilization of IDL
  • with equimolar elevation of plasma total cholesterol and TAG measurements

Clinical: xanthomas and accelerated coronary and peripheral vascular disease (develop in pts by middle age)

GI (17 decks)

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