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HES Biochem > Lecture 10 - Fat Metabolism > Flashcards

Lecture 10 - Fat Metabolism Flashcards

1
Q

What are the 3 ways that vertebrates obtain fat for use as a fuel source?

A

1) Obtain fat from the diet
2) Mobilize fat from adipose tissue
3) The liver converts excess dietary carbohydrates to fats for export to other tissue

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2
Q

Pancreatic Lipase

1) Where is it located?
2) What does it do?

A

1) Intestinal lumen

2) Absorption of FA from diet into intestine

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3
Q

Lipoprotein Lipase

1) Where is it located?
2) What does it do?

A

1) Capillary walls

2) Absorption of FA from chylomicrons and VLDL into target tissues

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4
Q

Hormone sensitive Lipase

1) Where is it located?
2) What does it do?

A

1) Intracellular

2) Breaks down cellular fat stores in adipose tissue

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5
Q

What is the role of bile salts?

A

Bile salts are derivatives of cholesterol. They are produced in the liver and stored in the gallbladder. They emulsify fats in the small intestine, breaking up the fat droplets and surrounding them so they form micelles that can now be acted upon by lipases

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6
Q

What is the purpose of lipoproteins?

A

They transport fats from the small intestine (chylomicrons) or liver (VLDL) in the blood so that the fat can be delivered to bodily tissues

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7
Q

Describe the structure of a lipoprotein (general)

A

The center consists of triacylglycerols, cholesterol, and cholesteryl esters. FAs are in form of phospholipids, so phospholipid heads are on outer surface. Outer surface also contains apolipoproteins which coat the surface and confer specific functions/fates to the lipoprotein.

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8
Q

Arrange the lipoproteins from lowest density to highest.

A 
Chylomicrons
VLDL
IDL
LDL
HDL
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9
Q

Arrange the lipoproteins from lowest protein content to highest.

A 
Chylomicrons
VLDL
IDL
LDL
HDL
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10
Q

Arrange the lipoproteins from lowest fat content to highest.

A 
HDL
LDL
IDL
VLDL
Chylomicrons
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11
Q

Arrange the lipoproteins from smallest to largest.

A 
HDL
LDL
IDL
VLDL
Chylomicrons
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12
Q

What is the function of chylomicrons?

A

Dietary lipids absorbed in the intestines are packaged with dietary cholesterol into chylomicrons, which then transport dietary fat to the tissues and dietary cholesterol to the liver.

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13
Q

What is the function of VLDL?

A

TAGs and cholesterol that are synthesized de novo in the liver are packaged into VLDL, which then deliver endogenous FAs and cholesterol to tissues.

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14
Q

Are ApoB apolipoproteins exchangeable or non-exchangeable?

A

Non exchangeable

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15
Q

ApoB 100 is found in lipoproteins from the ___

ApoB48 is found in lipoproteins from the ___

A

Liver

Intestines

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16
Q

What are the 2 functions of HDL?

A

1) serves as reservoir for exchangeable apolipoproteins

2) Plays important role in cholesterol transport

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17
Q

ApoB100 is found on which lipoprotein(s)?

What is its function?

A

VLDL, IDL and LDL

It is a weak ligand for receptor mediated clearance

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18
Q

ApoB48 is found on which lipoprotein(s)?

A

Chylomicrons

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19
Q

ApoC-II is found on which lipoprotein(s)?

How is it acquired? What is its function?

A

VLDL and chylomicrons

Acquired from HDL
Promotes binding of lipoproteins to lipoprotein lipase (LPL)

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20
Q

ApoE is found on which lipoprotein(s)?

How is it acquired? What is its function?

A

IDL and chylomicron remnants

Acquired from HDL
High affinity ligand for receptor mediated clearance by LDL receptor

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21
Q

Describe the metabolism of chylomicrons.

How are the products of chylomicron metabolism used in the muscle? In the adipose tissue?

A

Dietary TAGs are absorbed in intestine and packaged with dietary cholesterol in chylomicrons, which then enter circulation via lacteals to the lymphatic system. Chylomicrons circulate through body. While circulating, chylomicrons interact with HDL and acquire ApoC-II. When reach capillaries of target tissues, ApoC-II facilitates interaction with LPL which hydrolyzes the stored TAGs into FAs and glycerol. In the muscle, the FAs are oxidized for energy. In adipose tissue, the FAs are re-esterified and stored as TAGs. The TAG depleted chylomicron remnant then interacts with HDL in the blood again and exchanges ApoC-II for ApoE. The remnant then travels to the liver where the ApoE facilitates uptake into the liver. The stored cholesterol and apolipoproteins are recycled.

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22
Q

Describe the metabolism of VLDL

A

FAs produced via FA synthesis in the liver are packed into VLDL. Circulating VLDL interacts with HDL and acquires ApoC-II, which facilitates interaction with LPL at target tissues. Once at target tissues, LPL hydrolyzes TAGs in VLDL to FAs and glycerol. As this occurs, VLDL loses FA content and interacts again with HDL to exchange ApoC-II for ApoE, becoming an IDL. Remaining 50% of the IDL is taken back up by the liver and 50% continues to be metabolized by tissues. As this occurs, the density again increases and the particle becomes an LDL. Once an LDL, the particle interacts again with HDL and loses ApoE (retains ApoB100). The LDL the interact with surface receptors via ApoB100 and are slowly taken up into the tissues.

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23
Q

Describe LDL uptake in cells.

A

Surface LDL receptors recognize ApoB100. They bind to the LDL and internalize the LDL in vesicles which fuse with lysosomes to hydrolyze the contents of the LDL. Free cholesterol and FA are released into the cytosol and the LDL receptors are returned to the surface. The released cholesterol goes to the ER where it signals to the cell to reduce the transcription of HMG-coA reductase and LDL receptors and increase the transcription of ACAT.

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24
Q

Why is LDL considered bad cholesterol?

A

High [LDL] in the blood has been shown to be a major factor in atherosclerosis (accumulation of lipids in blood vessel walls).

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25
Q

What is ACAT?
Where is this enzyme located?
Why is it beneficial?

A

ACAT catalyzes the transfer of fatty acids to cholesterol to form cholesteryl esters.

This enzyme is located in the liver.

Beneficial b/c cholesteryl esters are more hydrophobic than cholesterol, so they can be packed more tightly into lipoproteins.

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26
Q

How does HDL play a role in cholesterol transport?

A

Circulating HDL extract excess cholesterol from cell-surface membranes. They transport the cholesterol to the liver where it is converted to bile salt.

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27
Q

Describe how stored TAGs are mobilized from adipose tissue when fuel stores are low.

A

When fuel stores are low (fasted state), the hormones driving metabolism are glucagon (pancreas) and epinephrine (adrenal medulla). These hormones activate hormone sensitive lipase to break down TAGs into free FAs and glycerol. The FAs enter the blood stream and bind to serum albumin, which allows them to travel to target tissues via the blood.

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28
Q

Once FAs reach target tissues, they undergo Beta oxidation. Describe this process.

(1) Activation
(2) Transport into mitochondria
(3) Beta Oxidation
(4) Fates of molecule produced

A

1) When the FA enters the tissue, the FA is delivered to the cytosol. In the cytosol, acyl-coA synthetase catalyzes the reaction FA + coA-SH + ATP –> Fatty Acyl-coA + AMP + PPi. The PPi is hydrolyzed to 2Pi releasing energy that drives the reaction forward.
2) Activated FA-coA is transferred to carnitine via carnitine palmitoyl transferase I. The Acyl carnitine is shuttled across the mitochondrial membrane via a carnitine transporter. Carnitine palmitoyl transferase II in the matrix transfers the fatty acyl group from carnitine to a coA-SH once again and the carnitine returns to the cytosol via the transporter.
3) The Fatty acyl-coA undergoes oxidation of the beta carbon, releasing the 1st two carbons of the FA chain as acetyl coA. The electrons from the oxidation are transferred to FAD and NAD+ to produce 1 FADH2 and 1 NADH.
4) The acetyl coA produced can then enter the CAC since they are both in the matrix. The NADH and FADH2 can enter the ETC since they are also in the matrix and ETC is on inner membrane.

29
Q

Describe the energy totals for beta oxidation.

A

1 FADH2 is produced (yields 1.5 ATP via ETC), 1NADH is produced (yields 2.5 ATP via ETC) and 1 acetyl coA is produced (yields 3 NADH, 1 FADH2 and 1 GTP for total of 10 ATP after ETC). Thus grand total is 1.5 + 2.5 + 10 = 14 ATP.

30
Q

Let’s say there is a FA that has 17 carbons. How many acetyl coA will be produced? What will happen with the last 3 carbon structure?

A

7 Acetyl coAs would be produced. The remaining 3 carbon structure is propionyl coA which can be converted to succinyl coA (intermediate of CAC). Thus, oxidation of odd chain FAs results in increased CAC activity.

31
Q

How does energy state regulate beta oxidation?

A

High levels of NADH/NAD+ inhibits enzymes of beta oxidation

32
Q

How do hormones regulated Beta oxidation?

A

Hormone sensitive lipase, which produces the FAs for beta oxidation, is regulated by hormones. Increased glucagon and epinephrine result in increased cAMP production via GPCR signaling. This results in increased phosphorylation of perilipin and HSL, resulting in increased activity of HSL and increased FAs made available for Beta oxidation.

33
Q

How is beta oxidation transcriptionally regulated?

A

PPAR family of nuclear receptors with fatty acid ligands act as transcriptional factors. They are triggered when there is an increased demand for energy.

34
Q

How does perilipin act to control HSL activity?

A

Under normal conditions, perilipin surrounds globular fat in adipose tissue to prevent HSL from degrading TAGs. When perilipin is phosphorylated (occurs via glucagon and epinephrine binding to GPCR, activates AC, increases cAMP, increases PKA activity, phosphorylates perilipin) this signals to HSL to come and start digesting the TAGs and perilipin allows access of HSL to the globular fat stores.

35
Q

Where does FA degradation occur? FA synthesis?

A

Degradation: mitochondrial matrix
Synthesis: cytosol

36
Q

What is the role of NAD+/NADPH in FA degradation and synthesis?

A

Degradation: NAD+ accepts e- to produce NADH
Synthesis: NADPH donates e- to produce NADP+

37
Q

What is the energy cost of FA degradation? What is the energy cost in FA synthesis?

A

Degradation: 2ATP utilized for activation of acyl group
Synthesis: 1 ATP utilized for every acetyl coA incorporated into growing FA chain

38
Q

What tissues can perform FA degradation? What tissues can perform FA synthesis?

A

Degradation: Most tissues
Synthesis: Mostly liver, some in adipose tissue

39
Q

Acetyl coA is the starting material for FA synthesis and for the CAC. Under what conditions will acetyl coA be converted to FAs as opposed to being utilized by the CAC?

A

If energy levels are high (i.e. ATP/ADP ratio and NADH/NAD+ ratio are high) then acetyl coA will be stored rather than broken down

40
Q

Acetyl coA that is produced in the mitochondria from PDH complex must be transported to the cytosol for FA synthesis. Describe this process.

A

Acetyl coA combines with OAA to form citrate via citrate synthase. Citrate is shuttled through membrane via tricarboxylate transport system. Then in cytosol, citrate is converted back to OAA and acetyl coA by ATP-citrate lyase.

41
Q

1st step of FA synthesis

1) reactants?
2) Products?
3) Enzyme that catalyzes reaction?
4) Energy cost?
5) Why is this step important?

A

1) Acetyl coA + HCO3- + ATP
2) Malonyl coA + ADP + Pi
3) Acetyl coA carboxlase
4) Uses 1 ATP per acetyl coA added to FA chain
5) This is the rate limiting step of FA synthesis

42
Q

What is fatty acid synthase (FAS)?

A

Mutlifunctional protein made of single polypeptide chain with multiple active sites

43
Q

What is the role of the ACP arm in FAS?

A

ACP acts as a flexible arm carrying intermediates from one active site to another. ACP arm moves the growing FA chain between active sites for various reactions that take place on enzyme. It is also where new maloney coA is added. Once it brings FA chain through one round of reactions, it leaves the FA chain on the KS subunit. Then, when new malonyl coA is added to ACP arm, the arm swings and grabs the FA chain and adds its new malonyl coA to the FA chain.

44
Q

How many NADPH are required per malonyl coA added to FA chain by FAS?

A

2 NADPH per malonyl coA

45
Q

Summarize the energy requirements of FA synthesis for palmitate (16C FA chain)

A

8 acetyl coA
7 ATP (in production of malonyl coA)
14 NADPH + 14 H+

46
Q

Why are some FAs considered essential?

A

The human body cannot incorporate double bonds beyond carbon 9. Thus, some FAs must be obtained from the diet b/c they cannot be de-saturated by the human body. Once obtained from the diet, the essential FAs are metabolized to other products from there.

47
Q

How does energy state regulated FA synthesis?

A

When energy supply is high, any excess carbon from carbohydrates or amino acid catabolism will be directed toward FA synthesis and stored as TAGs.

48
Q

Which enzyme in FA synthesis is allosterically regulated? How?

A

Acetyl coA carboxylase

Citrate: High [citrate] signals high energy state, thus this stimulates FA synthesis

Palmitoyl coA: high [palmitoyl coA] signals that there are excess FAs, thus this inhibits FA synthesis

49
Q

How does phosphorylation/dephosphorylation affect acetyl coA carboxylase activity?

A

Phos/Dephos is triggered by hormones, glucagon would inhibit FA synthesis (phosphorylate acetyl coA carboxylase) and insulin would stimulate FA synthesis (dephos acetyl coA carboxylase)

50
Q

What role does malonyl coA play on regulation of FA oxidation?

A

Malonyl coA presence will inhibit carnitine acyl transferase. This is important because if this did not occur, then the FAs produced from FA synthesis could be transferred right back into the matrix for degradation. Thus, when FA synthesis is occurring, FA degradation is necessarily inhibited.

51
Q

What are the 2 possible fates of FAs that are synthesized or ingested?

A

1) Incorporated into TAGs for storage

2) Incorporated into phospholipid component of membranes

52
Q

Which enzyme catalyzes the conversion of DHAP into glycerol-3-phosphate?

A

Glycerol-3-phosphate dehydrogenase

53
Q

What effect does insulin have on dietary carbohydrates and AAs in relation to fat?

A

Insulin stimulates the conversion of excess glucose and AAs into fatty acids by stimulating the production of acetyl coA and the conversion of acetyl coA into fatty acids

54
Q

What are the 3 important uses of cholesterol?

A

1) Incorporation into cell membranes
2) Precursor for steroid hormones
3) Precursor for bile acids

55
Q

Briefly describe cholesterol biosynthesis

A

2 acetyl coA combine to form acetoacetyl-coA, which is then converted to HMG-coA, which is then coverted to mevalonate by HMG-coA reductase. This enzyme is the rate limiting step of cholesterol synthesis. Phosphate groups are transferred to mevalonate from ATP to form an activated complex which is then used to build the sterol structure.

56
Q

Cholesterol synthesis is ___ by insulin, ___ by glucagon

A

stimuated, inhibited

57
Q

How does intracellular [cholesterol] regulate cholesterol synthesis?

A

High intracellular cholesterol transcriptionally downregulates HMG-coA reductase and increases degradation of HMG coA reductase

58
Q

What is SREBP?

A

Sterol Regulatory Element Binding Protein

59
Q

What is SCAP?

A

SREBP Cleavage Activating Protein, acts as sterol sensor

60
Q

How do SREBP and SCAP work to regulate cholesterol synthesis?

A

When cholesterol is high, SREBP is secured in ER b/c it is bound to SCAP. When cholesterol is low, there is a conformational change in SCAP that releases SCAP-SREBP to the Golgi, where proteases cleave SREBP to release an active binding domain. This active binding portion migrates to the nucleus where it binds to DNA and regulates the transcription of HMGcoA reductase and LDL receptors. Since this is activated in low cholesterol situation, it upregulates the transcription of these genes.

61
Q

Statins are a competitive inhibitor of ___

A

HMG coA reductase

62
Q

How do statins function to lower cholesterol in the blood?

A

1) Inhibit HMG co A reductase, thus decreasing endogenous production of cholesterol
2) Increase transcription of LDL receptors, which leads to increased uptake of LDL and decreased LDL + cholesterol in the blood

63
Q

What are the 2 possible fates of acetyl coA produced from fatty acid oxidation?

A

1) Enter CAC

2) Produce ketone bodies

64
Q

What are the 3 ketone bodies produced? What are their fates?

A

1) Acetone (exhaled)
2) Acetoacetate
3) Beta - hydroxybutyrate

2 and 3 are secreted in the blood and travel to extrahepatic tissue and are used for energy. They are used b/c ketone bodies are converted back into acetyl coA in target tissues and then enter CAC

65
Q

Under what conditions are ketone bodies used for energy?

A

Starvation

66
Q

What tissues benefit from using ketone bodies?

A

BRAIN
Heart
Skeletal muscle
Kidney

67
Q

Describe the circumstances under which acetyl coA will be used for ketone body production over CAC

A

In condition of starvation, lipolysis of fat stores is high. A lot of acetyl coA is produced and gluconeogenesis is occuring. B/c gluconeogenesis requires ATP, it can only run for so long. This process also depletes OAA from the CAC b/c OAA can be used to form glucose. Thus, when gluconeogenesis and the CAC have been running, eventually the CAC will not be able to continue due to depletion of OAA and the [acetylcoA] will build up. This acetyl coA will then be used to produce ketone bodies.

68
Q

What happens in periods of severe starvation, when ketone bodies are being produced abundantly?

A

Blood pH will drop and coma and death can result (ketoacidosis)

HES Biochem (11 decks)

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