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Scientific Foundations > Lecture 52 > Flashcards

Lecture 52 Flashcards

Cholesterol Metabolism

1
Q

cholesterol metabolism overview

A
  • most cells can synthesize cholesterol
  • liver, intestine, and steroidogenic tissues (adrenal cortex, testes, ovaries) contribute most significantly to the overall cholesterol pool
  • liver is the central organ that controls the overall cholesterol homeostasis (synthesis, distribution, elimination)

pg 1351

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2
Q

sources of liver cholesterol

A
  • diet (from chylomicron remnants)
  • de novo synthesis (from acetyl CoA)
  • delivered via HDLs (reverse cholesterol transport) -> collect excess cholesterol from peripheral tissues

pg 1351

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3
Q

routes for cholesterol clearance from the liver

A
  • secretion into VLDL/LDL (sent back to peripheral tissues for membrane structure/function)
  • secretion as free cholesterol into the bile (emulsification of fats)
  • conversion to bile salts and acids (only way we can clear from body)

pg 1351

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4
Q

3 protein transporters for cholesterol

A
  • Niemann-Pick type C1 (NPC1): integral membrane protein in late endosomes/lysosomes that transfer LDL-cholesterol from lysosomes to other cellular compartments (ER, PM, etc)
  • Niemann-Pick type C2 (NPC2): ubiquitously expressed soluble protein in the lysosomal lumen that transfer cholesterol to NPC1
  • Niemann-Pick like type C1 (NPCL1): a protein responsible for dietary cholesterol and biliary cholesterol absorption expressed in small intestines as well as in hepatocytes

pg 1352

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5
Q

ezetimibe

A

blocks NPCL1 and inhibits the absorption of dietary cholesterol and decreases the amount of cholesterol available to liver cells, used as cholesterol lowering drug

pg 1352

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6
Q

liver cholesterol synthesis de novo

A
  • multiple steps divided into 6 stages
  • stage 1: synthesis of HMG CoA
  • stage 2: synthesis of mevalonate
  • stages 3-6: synthesis of cholesterol
  • enzyme localization: cytosol, smooth ER membranes, peroxisomes

pg 1353

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7
Q

liver synthesis stages 1 and 2

A
  • stage 1: 2 acetyl CoA -> acetoacetyl CoA (using thiolase) -> HMG-CoA (using HMG CoA synthase)
  • stage 2: HMG-CoA -> mevalonate (uses NADPH, HMG CoA reductase)
  • rate limiting committed step: HMG-CoA reductase -> key regulated irreversible step, integral membrane protein of ER facing the cytosol
  • produces mevalonate

pg 1354

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8
Q

regulation of HMG-CoA reductase activity

A
  1. regulation at the level of enzyme protein product (sterol-dependent) -> enzyme gene expression, enzyme degradation (transcriptional regulation, how much enzyme will be produced)
  2. regulation via covalent modifications (sterol-independent) -> phosphorylation/dephosphorylation

pg 1355

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9
Q

transcription factor SREBP-2

A
  • integral protein of the ER membrane
  • associated with a 2nd ER membrane protein, SCAP (SREBP cleavage-activating protein), which has a sterol-binding domain (INSIG)
  • once released, it translocates to the nucleus and binds DNA at the cis-acting sterol regulatory element (SRE) upstream of the HMG CoA reductase gene -> activates gene expression

pg 1356

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10
Q

regulation -> high cholesterol

A
  • high sterol levels -> NO new sterols needed
  • SCAP binds sterols and retains the SCAP-SREBP complex on the ER in an inactive state
  • indirectly cause HMG CoA redutase to be ubiquinated, thus targeted for degradation by proteasomes

pg 1357

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11
Q

regulation -> low cholesterol

A
  • low sterol levels -> new sterols NEEDED
  • SCAP protein is not bound to sterols (they are low)
  • SCAP-SREBP-2 complex is transported to the golgi
  • in golgi, SCAP is cleaved to release SREBP-2
  • free SREBP-2 moves to the nucleus where it binds an SRE and initiates transcription of HMG CoA reductase

pg 1358

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12
Q

regulation via covalent modifications

A

activity is influenced by the energy state of the cell:

  • elevated AMP (low energy): HMG CoA reductase is phosphorylated, which is its INACTIVE form (high glucagon: fasting or glucocorticoids: stress)
  • elevate ATP (high energy): HMG CoA reductase is dephosphorylated, which is its ACTIVE form (high insulin and thyroxine, well-fed state)

pg 1359

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13
Q

statin drugs

A
  • contain a side group that resembles HMG CoA
  • compete for the active site of the HMG CoA reductase enzyme (competitive inhibition)
  • helpful in lower cholesterol in bloodstream by blocking rate-limiting step

pg 1360

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14
Q

cholesterol synthesis: stage 3

A
  • mevalonate to isoprenyl pyrophosphates (IPP)
  • loss of CO2, 3 ATP
  • requires ATP
  • works to keep molecules water soluble

pg 1361

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15
Q

cholesterol synthesis: stages 4-6

A
  • 4: isoprenyl pyrophosphates -> squalene
  • 5: squalene -> lanosterol
  • 6: lanosterol -> cholesterol (inborn error of metabolism)

pg 1361

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16
Q

cholesterol synthesis: stages 3-6

A
  • phosphorylation of mevalonate and presence of pyrophosphate in subsequent structures help keep these water-insoluble compounds in solution
  • pyrophosphate is released in each of 4 condensation steps, making the reactions irreversible
  • beginning with squalene, intermediates in cholesterol biosynthesis are nonphosphorylated and are so hydrophobic that they require an intracellular sterol carrier protein to keep them soluble

pg 1361

17
Q

FPP is a chemotherapeutic target

A
  • farnesyl pyrophosphate (FPP)
  • responsible for farnesylation -> so chemotherapy works to block this
  • FPP links Ras (small GTP-binding protein) to the membrane
  • Ras mutations are seen in 1/3 of human cancers

pg 1362

18
Q

Smith-Lemli-Opitz syndrome

A
  • defect in the conversion of lanosterol to cholesterol (step [8]: 7-dehydrocholesterol reductase)
  • autosomal recessive
  • symptoms: intellectual delay, ambiguous genitalia, hypotonia, microcephaly, syndactyly, limb abnormalities/deformities, polydactyly

pg 1362

19
Q

required substrates for cholesterol synthesis

A
  1. acetyl CoA - C skeleton
  2. NADPH - reducing equivalents
  3. ATP - energy needed

pg 1363

20
Q

under what conditions will de novo synthesis of cholesterol be active?

A
  • in well-fed state (when ALL substrates are available)
  • when cholesterol supply is low

pg 1363

21
Q

cholesterol degradation and clearance

A
  • humans canNOT degrade the sterol nucleus to CO2 and H2O
  • excreted into the bile as cholesterol or converted to bile acids and salts and excreted
  • very little loss (5% daily in feces) due to the efficiency of enterohepatic circulation of bile salts

pg 1364

22
Q

bile salts and bile acids

A
  • during production of bile acids from cholesterol, a number of oxygen atoms have been added, which increases the solubility of the compound
  • in the final transformation from a bile acid to a bile salt, one of two amino acids (glycine or taurine) are added to the bile acid to form bile salt, which even further increases the solubility
  • the final compounds are amphipathic in nature, and so acts as an emulsifying agent on lipids (including cholesterol)

NEED TO SEE NEW SLIDE IN BB

pg 1365

23
Q

enterohepatic circulation of bile

A
  • bile acids (from cholesterol) converted to bile salts by addition of AA in liver
  • bile salts travel through bile duct to duodenum
  • about 5% of bile salts lost through fecal excretion per day, the rest go back to the liver via the portal vein

pg 1366

24
Q

bile sequestrants and LDL cholesterol

A
  • Cholestyramine is a bile acid sequestrant, which binds bile in the GI tract to prevent its reabsorption and promote excretion
  • removal of bile form the liver relieves inhibition on bile acid synthesis and promotes diversion of cholesterol to bile salts
  • dietary fiber may also act as a kind of natural bile acid sequestrant

pg 1367

25
Q

cholelithiasis (gallstones)

A
  • derived from cholesterol and result from too little bile salts and/or too much cholesterol (the bile salts are required to solubilize free cholesterol)
  • possible causes…
  • inefficient enterohepatic cycling of bile salts
  • liver dysfunction resulting in bile salts deficiency
  • other idiopathic reason for decreased bile salts

pg 1368

Scientific Foundations (46 decks)

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