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2.2 Metabolism Biochem > Fat Digestion, Storage, Cholesterol > Flashcards

Fat Digestion, Storage, Cholesterol Flashcards

1
Q

Where does triglyceride metabolism start in the digestive tract?

A

-intestine

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2
Q

What products initially begin breakdown of lipids?

A
  • liver makes bile for emulsification (micelle formation)

- Pancreas secretes LIPASE and COLIPASE to break down TGs

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3
Q

What is the function of Colipase?

A
  • binds Lipase, shifts pH optimum to ~6, allows it to work better
  • also prevents denaturing in bile
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4
Q

Describe the function of pancreatic lipase.

A
  • Clips 2 FA off a TG @ positions 1 and 3
  • leaves 2-Monoacylglyerol

-these 2 forms can now cross the intestinal brush border, where they re-form TG in the cell

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5
Q

Describe the function of Chylomicrons.

A
  • secreted from INTESTINAL EPITHELIUM
  • goes into lymph, enters blood thru thoracic duct
  • carries DIETARY TGs to peripheral tissues
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6
Q

What are the causes of steatorrhea and the stool findings?

A
  • decreased bile (TG in shit)
  • decreased pancreatic function (TG in shit)
  • malabsorption (FA in shit)
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7
Q

Describe the GENERAL path of hi glucose to adipose deposition.

A
  • (IN LIVER)
  • hi glucose, hi acetyl CoA
  • excess Acetyl CoA made to FA
  • FA made to TG
  • TG moved in VLDLs to adipose tissue
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8
Q

What enzyme is key in regulation of FA synthesis?

A

-Acetyl CoA Carboxylase

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9
Q

What are the requirements for the key enzyme in FA synthesis?

A
  • ATP, Biotin, CO2

- (its 1 of 3 ABC carboxylases!)

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10
Q

What are the 3 enzymes that are ABC carboxylases?

A
  • Pyruvate Carboxylase (gluconeogenesis; pyruvate–>OAA)
  • Acetyl CoA Carboxylase
  • 3rd one, look up
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11
Q

What reaction is key to regulation of FA synthesis?

A

-Acetyl CoA into Malonyl CoA

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12
Q

The conversion of Malonyl CoA into FA is regulated by what, and requires what cofactors?

A
  • FA Synthase (no shit!)

- needs NADPH

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13
Q

What is the ONLY fatty acid that can be synthesized by the body from scratch?

A

-Palmitate (16 C, no double bonds)

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14
Q

How do other fatty acids form from palmitate in the liver?

A

-they are modified by enzymes in the ER that add dbl bonds, or add/delete C’s

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15
Q

What two signals stimulate FA synthesis by activating its key enzyme?

A
  • INSULIN induces trascription of Acetyl CoA Carboxylase

- cytoplasmic CITRATE will allosterically activate Acetyl CoA Carboxylase

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16
Q

What product of the TCA cycle must move from the matrix, across the inner mitochondrial membrane, and into the cytosol for FA synthesis to occur?

A

-Citrate!

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17
Q

Describe the pathogenesis of fatty liver in alcoholics.

A

EtOH disrupt assembly of VLDLs in the liver, which results in fatty deposition of TGs+cholesterol

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18
Q

Lipases and Phospholipases cleave what type of bond on what molecules

A

-cleave ESTER bonds of TGs and phospholipids, respectively

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19
Q

Differentiate between Phospholipase A1, A2, and C

A
  • A1 cleaves 1st FA
  • A2 cleaves 2nd FA
  • C cleaves btw DAG and IP3
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20
Q

Describe the difference in cholesterol and cholesterol esters.

A
  • cholesterol (able to be absorbed into mucosa)
  • cholesterol esterases have a FA attached, must be cleaved by PANCREATIC ESTERASE to be absorbed
  • gut cell will reform them into CEs for shipping
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21
Q

What apolipoprotein is essetial for carrying cholesterol ESTERS and TGs from the diet and into the blood?

A
  • Apo B-48

- needed for Chylomicron assembly

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22
Q

What pathology is associated with the essential apolipoprotein for dietary TG and cholesterol transport?

A
  • Abetalipoproteinemia (no B-48)

- AR mutation in MTP gene; failure to thrive, lipid accumulation in enterocytes

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23
Q

When the chylomicron exits the lymph and enters the blood, what key process occurs?

A
  • the chylomicron gets a gift from HDL

- HDL donates Apo-E and Apo-C to the chylomicron

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24
Q

Describe the process of Chylomicron emptying.

A
  • Apo-C is the trigger for activation of LPL (lipoprotein lipase)
  • chylomicron dumps its passengers into the Adipose tissue via LPL
  • chylomicron re-gifts the Apo-C to HDL
  • now we have a teeny little CHYLOMICRON REMNANT
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25
Q

What apolipoprotein is involved in chylomicron remnant degredation?

A

-ApoE’s function is to allow chylomicron remnant uptake into liver

(apoE=EXIT from blood)

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26
Q

Describe the process of chylomicron remnant degredation in the liver.

A
  • endocytosis of remnant
  • endosome+primary lysosome fusion=2 lysosome
  • enzymes in secondary lysosome break down the little bit of TG and cholesterol esterase left inside
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27
Q

For all practical purposes, where do dietary TGs and cholesterol end up?

A
  • dietary TGs to the adipose tissue

- dietary cholesterol to liver

28
Q

What the heck does the liver do with all the FA it made from extra glucose and the cholesterol it got from breaking down chylomicrons?

A

-it ships it as a VLDL

29
Q

What apolipoprotein is found immediately on a VLDL?

A

-Apo-B100

30
Q

What apolipoproteins are gifts from HDL to VLDL?

A

-ApoC and E

just like the gifts from HDL to chylomicrons

31
Q

Chylomicron is to B-48 as VLDL is to?

A

B-100

32
Q

VLDL is the liver as Chylomicron is to?

A

-Enterocyte

33
Q

Chylomicron is to Cholesterol Esterase as VLDL is to?

A

Cholesterol

not esterified to a FA since it comes from liver

34
Q

VLDL is to IDL as chylomicron is to?

A

chylomicron remnant

35
Q

Describe the 2 fates of IDL.

A
  • can enter liver for degredation (via Apo-E; exit)

- can lose Apo-E and become an LDL

36
Q

How does IDL get cholesterol esterase?

A
  • IDL gives cholesterol to HDL
  • HDL has Apo-A, which calls LCAT over
  • LCAT converts cholesterol to CE
  • CE is given back to IDL
  • now IDL drops its ApoE and becomes LDL
37
Q

LDL’s primary function is what?

A

-to deliver its cholesterol esterase contents to peripheral tissues

38
Q

Describe the process of LDL dropping off its cholesterol esterases.

A
  • LDL-R binds to SINGLE COPY of Apo-B100 of LDL
  • endocytosis, clathrin coated pits
  • lo pH dissoctiates R and LDL, R is recycled
  • esterase cleaves CE into cholesterol
  • now cell has higher levels of cholesterol!
39
Q

Cholesterol inside a cell can really screw with the membrane fluidity, so its tightly regulated. What is cholesterol synthesized from (de novo), and what is the key enzyme?

A
  • from Acetyl CoA (from glucose)

- HMG CoA Reductase

40
Q

What 3 processes are affected by hi levels of intracellular cholesterol to prevent accumulation inside the cell?

A
  • inhibit HMG CoA Reductase (block de novo synthesis)
  • activation of ACAT (esterifies chol with FA, ability to be stored)
  • inhibition of LDL-R expression (downregulation)
41
Q

What is the difference between LCAT and ACAT?

A
  • LCAT circulates in the blood; interacts with Apo-A on HDL so it can create CE from cholesterol
  • ACAT is INTRACELLULAR; it creates CE from cholesterol so it can be stored away and do no harm to the cell membrane
42
Q

What familial hyperlipidemia involves a screwed up copy of the LDL receptor?

A
  • Type IIa familial hypercholesterolemia

- no cholesterol in cells, so they start to make it themselves (this exacerbates the hypercholesterolemia!)

43
Q

How does LDL become oxidized LDL (oxLDL)?

A
  • free radicals in the blood from oxygen are floating around looking for electrons
  • they can grab some e from Apo-B100 on LDL molecules
44
Q

What is the pathological manifestation of oxLDL?

A
  • oxLDL is NOT RECOGNIZED by the LDL-R

- now there is excess LDL in the blood

45
Q

Describe the pathogenesis of a atherosclerotic plaque.

A
  • oxLDL gets into tunica intima via endothelial dmg
  • scavenger R on Macrophage eats oxLDL since its recognized as foreign
  • macrophages keep eating oxLDL, become FOAM CELLS
  • foam cells die, spill out oxLDL, which deposits
  • get inflammation, process continues (fatty streak)
46
Q

Describe how HDL is a scavenger of cholesterol from peripheral tissue.

A
  • HDL can pick up peripheral cholesterol
  • will be esterified (due to Apo-A and LCAT in circulation)
  • CE is then either transferred to IDL, or given back to liver
47
Q

How do antioxidants prevent plaque formation?

A
  • Antioxidants (Vit E, beta carotene) will prevent the oxidation of LDL to oxLDL
  • no oxLDL=no plaques!
48
Q

Type I familial hyperlipidemia is a defect of what PROCESS?

A

-defect in Clearing out the Chylomicron/VLDL of their lipid components @ the peripheral tissues

49
Q

Type I familial hyperlipidemia can be a defect in what 2 genes?

A
  • either LPL
  • or Apo-C

-both involved in CLEARING out contents

50
Q

How will a patient present if they have no ability to Clear out their chylomicrons/VLDL @ peripheral tissues?

A
  • red/orange eruptive XANTHOMAS all over body
  • pancreatitis
  • fatty liver (hepatosplenomegaly)
  • hi Chylomicrons, and VLDL (after hi carb meal)
  • hi blood TG
51
Q

Type IIa familial hyperlipidemia is defect in what gene, and how is it inherited?

A
  • defective LDL receptor

- AD (homozygotes=very bad, hetero=bad)

52
Q

The two big ticket symptoms for a patient presenting with Type IIa hyperlipidemia (aka familial hypercholesterolemia) are?

A
  • Xanthomas of the Achilles tendon (et al)

- Corneal arcus (grey ring around cornea)

53
Q

What apolipoprotein and lipid are elevated in familial hypercholesterolemia, and why?

A
  • hi LDL (duh, no LDL-R)

- hi cholesterol (duh, LDL carries cholesterol esters)

54
Q

The #1 enzyme of cholesterol synthesis is ____________ and where in the cell is it located?

A
  • HMG CoA Reductase

- ER of cell

55
Q

HMG CoA Reductase, along with most reductases, require what?

A
  • NADPH

- this is the source of electrons (reduce=gain of e)

56
Q

What reaction does HMG CoA reductase catalyze?

A

HMG-CoA –> Mevalonate (aka mevalonic acid)

57
Q

Name some products that come from Farnesyl Pyrophosphate (part of the cholesterol synthesis after HMGCoAR)

A
  • cholesterol (duh)
  • synthesis of CoQ (ETC)
  • synthesis of Dolichol PPi (N-glycosylation)
58
Q

Describe Dolichol PPi and its involvement in N-glycosylation.

A
  • proteins being made in ER network
  • sugars are placed on the N group of Asparagine (hence N glycosylation)
  • Dolichol PPi is what brings the sugar from the cytosol in the lumen of the ER
59
Q

What are the fates of cholesterol in the body, since it can’t be burned to CO2 and water?

A
  • steroid hormone synthesis
  • membrane component
  • synthesis of Vit D
  • bile acid component
60
Q

What is the key enzyme to know in bile acid synthesis (post-cholesterol)?

A

-7a-hydroxylase

61
Q

Describe the enterohepatic circulation of bile acids and the effects on bile synthesis.

A
  • most bile acids are reabsorbed in the gut
  • albumin carries them back into the liver
  • there they inhibit 7a-hydroxylase, which prevents synthesis of extra bile acids
62
Q

What are three substances that negatively influence HMG CoA Reductase?

A
  • cholesterol (via allosteric)
  • Glucagon (via Pi and reduced gene expression)
  • Statins
63
Q

What stimulates activity of HMG CoA Reductase?

A

-Insulin (thru chopping of a Pi)

64
Q

Statin drugs are ___________ inhibitors of HMG CoA R; __________ changes and __________ stays the same

A
  • Competitive
  • Km changes
  • Vmax does not change
65
Q

Connect HMG CoA Reductase side effects with its biochemistry.

A
  • Recall: choesterol, CoQ, and Dolichol PPi are all reduced with statins
  • CoQ is in the ETC (mitochondria); what has tons of mitochondria? MUSCLE AND LIVER

-therefore, can get rhabdomyolysis+hi liver enzymes

66
Q

Liver 7a-hydroxylase (invovled in bile acid synthesis) will increase in activity with the administration of what drug?

A
  • Bile acid sequestrants (ex: cholestyramine)

- reduced levels of enterohepatic circulating bile

67
Q

What malabsorptive pathology is associated with the inability to absorb chylomicrons into the lymphatics of the intestinal villi?

A

Whipple’s disease

2.2 Metabolism Biochem (6 decks)

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