Lipid Metabolism Flashcards

1
Q

What is the general structure of a triacylglycerol?

A

glycerol + 3 fatty acids

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2
Q

What is the general structure of a steroid?

A

4 carbon rings with R groups bound to rings (R group just means anything)

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3
Q

What is the general structure of a glycolipid?

A

glycolipid has a carbohydrate bound to the “head” of the glycolipid. Otherwise it is a pair of fatty acids bound to a polar nitrogenous head.

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4
Q

What is the general structure of a phospholipid?

A

phospholipid has a fatty acid tail, a phosphate bridge, and a nitrogenous head.

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5
Q

What is the general structure of a fatty acid?

A

A long chain of carbons and hydrogens, with a polar head. Can be saturated (all single bonds) or unsaturated (some double bonds). Double bonds can be cis (cause kinks) or trans (keep the molecule straight).

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6
Q

What lipid is used for energy storage?

A

Triacylglycerol! It’s efficient in terms of energy per unit weight, but it’s also super good for energy storage because it doesn’t require any hydration, whereas every gram of carbohydrate requires two grams of water for storage.

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7
Q

How does degree of unsaturation and size effect melting point for fats?

A

Melting point increases as length of fatty acid chain increases. Melting point decreases as degree of unsaturation increases. Trans double bonds cause less of a temperature decrease than cis. For a given length of fatty acid, the difference between cis and saturated can be 70 degrees!

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8
Q

Why are most fatty acids of even length?

A

Our fatty acid synthesis mechanisms add two carbon chains at a time, as do all animals. Since carbons are added 2 at a time, you always end up with an even chain fatty acid.

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9
Q

Where do odd-length fatty acids come from?

A

We don’t produce odd-length fatty acids, so they have to come in from the diet. We can’t digest odd-length fatty acids without an additional step that creates propionyl CoA and breaks it down to succinyl CoA (a step in the TCA cycle!) The succinyl CoA jumps straight into the TCA cycle to turn into succinate.

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10
Q

What are the alpha, beta, and omega carbons in a fatty acid?

A

The carboxyl carbon on a fatty acid is the 1st carbon. The next carbon (2nd) is the alpha carbon. The beta carbon is the 3rd carbon. This is where oxidation occurs (beta oxidation). The omega carbon is the last carbon on the fatty acid chain

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11
Q

Where are triacylglycerides stored?

A

Adipose cells are cells with basically giant vacuoles to hold lipids. Triacylglycerides form lipid droplets in the cell.

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12
Q

What issue arises with lipid digestion in the body?

A

The body is an aqueous environment. Lipids do not cope well in an aqueous environment. So the body needs to come up with a way to bring hydrophilic enzymes into interaction with hydrophobic lipids.

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13
Q

How does the body bring lipids and their regulatory enzymes together?

A

Lipid emulsification is defined as the process of maximizing the exposed surface area of lipids so enzymes can ultimately lead to lipid digestion. Emulsification has multiple pathways: chewing, intestinal peristalsis, and bile salts. These pathways maximize the availability of lipids for enzymes to interact with.

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14
Q

What enzymes digest lipids? How do they interact with the lipids?

A

Lipases break lipids down into smaller molecules. Lipases often utilize a colipase molecule to facility the interaction with lipids. Lipases are hydrophilic, but this colipase molecule has a hydrophobic domain for interacting with the lipid. It also binds the lipase and induces a conformation change. This conformation change pushes a regulatory domain away from the active site of lipase and allows lipase to begin digesting lipids.

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15
Q

Where does lipase come from?

A

It’s often made in the pancreas, the mouth, and the stomach.

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16
Q

What is the lipid emulsion composed of?

A

triacylglycerides, cholesterol, cholesterol esters. The clumps are coated with bile acids. Bile salts are ampipathic (have polar and nonpolar domains) and can interact with both environments.

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17
Q

What hormones regulate lipid digestion?

A

Cholecystokinin (CCK). CCK acts on the gall bladder to secrete bile and on the pancreas to secrete digestive enzymes (like lipase). The acidic chyme causes intestinal cells to secrete secretin, which induces the pancreas to release bicarbonate ion, which increases the pH to tolerable levels and helps lipase/other enzymes operate within their optimal pH.

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18
Q

Where are triacylglycerides digested? Where do their products go? How do they get there?

A

Triacylglycerides are digested in the liver, but their end products need to be sent all over the body. To get triacylglyceride products into the body (via blood flow), is no simple process. Lipase adds H2O to triacylglyceride and breaks it to form fatty acids and monoglycerols (one fatty acid remaining on the glycerol). These molecules are able to form micelles and sneak across the membrane. Once across the membrane they’re reformed into triacylglycerols. These triacylglycerols are packaged into chylomicrons, which are picked up by lacteals (special fatty acid product packages) and carried off through the blood.

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19
Q

What are the major steps for converting fatty acids to energy?

A

Triacylglycerols are degraded to fatty acids + glycerol by lipases (in adipose cells). Fatty acids are transported to the liver. Once in the liver, the fatty acids are activated (energy is added) and transported to the mitochondria. In the mitochondria these fatty acids are broken down into acetyl CoA, which is used up in the TCA cycle to produce energy.

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20
Q

How do hormones play a role in fatty acid digestion?

A

Glucagon and epinephrine both signal fatty acid digestion. Glucagon activity means you’re fasting, so glucagon wants to produce energy from non-glucose sources. Glucagon (or epinephrine) bind to a GPCR. This GPCR phosphorylates the alpha subunit of Gprotein. The alpha subunit activates adenylate cyclase, whch makes cAMP from ATP. cAMP leads to the activation of protein kinase A. Protein kinase A activates perilipin. Perilipin has two functions: restructure fat drops so that triacylglycerides are more accessible for reaction. Perilipin also induces release of cofactor for adipose triglyceride lipase. Adipose triglyceride lipase is used to degrade triacylglycerols

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21
Q

What is the overall structure change in triacylglycerol as it’s digested?

A

Turned into diacylglycerol by lipase, then turned into monoacylglycerol by lipase. monoacylglycerols + fatty acids can form micelles to travel out of the lumen (interior duct of the gastrointestinal tract) into mucosal cells, where it can be picked up by the lymph + circulatory systems.

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22
Q

What is adipose triglyceride lipase?

A

The main lipase used to digest triacylglycerides to diacylglyceride to monoacylglycerol. adipose triglyceride lipase is activated by perilipin (perilipin adds a coactivator).

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23
Q

What does perilipin do?

A

Perilipin is activated by the presence of glucagon or epinephrine (it’s phosphorylated by protein kinase A). Perilipin adds a coactivator to adipose triglyceride lipase which activators the lipase. Perilipin also phosphorylates hormone-sensitive lipase, which converts DAG to MAG

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24
Q

what is chanarin-dorfman syndrome?

A

A mutation in the coactivator for Adipose triglyceride lipase. AGTL doesn’t bind to the coactivator and isn’t able to break triacylglyceride to diacylglyceride. your liver gets huge because the triacylglyceride stuffs it up, you don’t have energy because you can’t digest fatty acids.

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25
Q

When triacylglycerides are broken down, what happens to the end products?

A

Glycerol is turned into pyruvate through glycolysis or glucose through gluconeogenesis.
Fatty acids turned into acetyl CoA through fatty acid oxidation and go through the TCA cycle to generate high energy electron carriers.

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26
Q

What are the overall steps for fatty acid metabolism?

A

fatty acids bind proteins that transport them from outside the cell into the cytoplasm. Once in the cell, fatty acids are activated to fatty acyl-CoA.
Carnitine transports fatty acyl CoA across the outer mitochondrial membrane, and then through to the inner mitochondrial matrix. Beta-oxidation occurs in the inner mitochondrial matrix, generating FADH2 and NADH while removing 2 carbons at a time in the form of acetyl CoA. Acetyl CoA generates NADH, GTP, and FADH2 through TCA. All these products go to the electron transport chain to create ATP. The acetyl CoA can also be used in the liver to generate ketone bodies.

27
Q

What is the activation step in fatty acid oxidation?

A

Fatty acids need to be activated by binding to coenzyme A. Fatty acyl CoA synthetase takes ATP and turns it into AMP to bind with the fatty acid (2 phosphates lost). It then acts again to replace the AMP with CoAsh, ultimately generating fatty acyl CoA.

28
Q

What is carnitine? What pathway is it relevant to?

A

Carnitine is a key molecule in the transport of fatty acids throughout a cell into the mitochondria for breakdown. Fatty acyl CoA is conjugated to carnitine to form acyl carnitine. Acyl carnitine is transported across the inner mitochondrial membrane by a protein carrier, translocase. The reaction is reversed inside the inner mitochondrial matrix to produce fatty acyl CoA and carnitine. The forward reaction (fatty acyl CoA + carnitine –> acyl carnitine) is catalyzed by carnitine acyl transferase 1. The reverse reaction is catalyzed by carnitine acyl transferase 2.

29
Q

How are fatty acids oxidized?

A

Oxidation of fatty acids occurs at the beta carbon (3rd carbon from the carboxyl end). Each beta oxidation releases two carbons in the form of acetyl CoA.

1: oxidation (add double bond to beta carbon) by FAD and acyl CoA dehydrogenase
2: enoyl CoA hydratase adds an alcohol to the beta carbon.
3: NAD+ and beta hydroxy acyl CoA dehydrogenase turn the beta carbon - alcohol into a carboxyl (oxidize)
4: beta keto thiolase splits Acetyl CoA group off of moecule

30
Q

What are the different size-dependent acyl CoA dehydrogenases?

A

long chain acyl-coa dehydrogenase = oxidize fatty acids between 12-18 carbons long.
medium chain acyl-coa dehydrogenase deals with fatty acids between 4-14 carbons in length.
short chain acyl-coA work on fatty acids with 4 or 6 amino carbon

31
Q

How is oxidation of unsaturated fatty acids different than saturated fatty acids?

A

Unsaturated fatty acids have double bonds, which acyl-CoA dehydrogenase may get tripped up by (depending on position). If the double bond is ever between the beta and 4th carbon, acyl-CoA dehydrogenase isn’t able to move forward. To compensate, an isomerase is used to move the double bond. The isomerase moves the double bond to be between the alpha and beta carbons. A reductase then reduces the double bond to a single bond, and acyl-CoA dehydrogenase continues.

32
Q

What order are the carbons in fatty acids oxidized?

A

Two at at time, always the alpha and carboxyl carbons leaving. So they’re lost from the “head” not the “tail”

33
Q

How are odd chain fatty acids digested?

A

The steps up until the very end are identical. At the end propionyl CoA is formed instea dof acyl CoA (3 carbons instead of 2). Propionyl CoA is turned to succinyl CoA (TCA cycle intermediate), which can be used for energy by the body. This conversion requires vitamin B12.

34
Q

Where are fatty acids oxidized?

A

Short chain fatty acids are digested in mitochondria in enterocytes in the small intestines. Long chain & branched fatty acids are digested in the peroxisomes of intestinal cells, to the point where they can be sent to the mitochondria for final touches.

35
Q

What toxic chemical is produced by peroxisomes during fatty acid digestion?

A

Hydrogen peroxide (oxygen is used up/turned into hydrogen peroxide h2o2 in the peroxisomes). Catalase (present in huge quantities in peroxisomes) converts hydrogen peroxide to water and oxygen.

36
Q

When does omega-oxidation of fatty acids occur?

A

If there’s ever a mutation or environment where beta oxidation cannot occur, fatty acid oxidation beginning at the omega end can occur. Omega methyl group is converted into an alcohol, and then into a carboxylic acid. The dicarboxylic acid product now has 2 “beta” carbons and the second one is open for oxidation activity.

37
Q

What is the overall yield of fatty acid metabolism?

A

Each cycle of oxidation (losing 2 carbons) produces 1 acetyl CoA, 1 FADH2 and 1NADH and 1 H+ (it takes 1 H2O as an input, since this is hydrolysis).
The last step in the cycle produces 2 acetyl CoA. And the first step required that the fatty acid become activated by 2 ATP.
So you get overall = 1+n acetyl CoA, n FADH2, n NADH, n H+, -2ATP. Unsaturated fatty acids are probably not as efficient since breaking the double bonds probably takes energy.

38
Q

What are the 3 ketone bodies?

A

acetoacetate, d-3-hydroxybutyrate, acetone

39
Q

What are ketone bodies used for?

A

They’re a crappy form of energy for the brain in times of starvation. They’re produced from fatty acids. When you don’t have oxaloacetate (needed in TCA, derivative of glucose) you can’t do the TCA cycle, so you need an alternative form of energy. Ketone bodies are formed from acetyl CoA, so they are the alternative.

40
Q

Where are ketone bodies formed? Where are they used?

A

Formed in the liver, used throughout the body in times of starvation (any organs or tissues that have high energy needs).

41
Q

How are ketone bodies formed?

A

Two acetyl CoA molecules –> (thiolase) –> acetoacetyl CoA + CoASH
Acetoacetyl CoA goes through a series of reactions to essentially lose the other CoA nad become acetoacetate. Acetoacetate can then be used to form acetone or d-beta-hydroxybutyrate.

42
Q

What dictates whether acetoacetone will become d-beta-hydroxybutyrate or acetone?

A

NAD+/NADH ratio in the cell. If you have a lot of NADH you’ll be pushed towards d-beta-hydroxybutyrate. If you have a lot of NAD+ you’ll be pushed away from d-beta-hydroxybutyrate. Acetoacetate –> acetone occurs spontaneously, so increased availability of acetoacetate increases amount of acetone.

43
Q

How are ketone bodies used as fuel sources?

A

depends on your starting ketone body. d-beta-hydroxybutyrate is oxidized to acetoacetate by NAD+. acetoacetate transfers a CoA group from succinyl CoA via succinyl CoA acetoacetate CoA transferase. Acetoacetate CoA goes through thiolase (added CoASH) to give you 2 acetyl CoA molecules. These are used as fuel.

44
Q

What is diabetic ketoacidocis?

A

In diabetes, insulin doesn’t work. So you can’t digest glucose or create oxaloacetate for the TCA cycle. Oxaloacetate is also used in fatty acid mobilization (needed for access to fatty acid-stored energy). Without either of these mechanisms, the body is sorely lacking in terms of energy. The body compensates by using ketone bodies as fuel. But ketones are acidic. Having tons of ketones around decreases your pH and can cause tissue damage/dysfunction.

45
Q

When does fatty acid synthesis occur? Where does it occur?

A

The most common time is when there’s an excess of calories and it needs to be stored somewhere. Carbohydrates are the main source of carbons for fatty acids. Fatty acids are synthesized in the livers and sent out to adipose cells for storage. Some disorders come from fatty acid transport issues, and liver becomes enlarged/damaged.

46
Q

Where in the cell does fatty acid synthesis occur?

A

In the cytoplasm.

47
Q

What is the starting reactant for fatty acid synthesis? Where is it found?

A

Acetyl CoA, and it’s found in the mitochondria.

48
Q

How does acetyl CoA get from the mitochondria to the cytoplasm to start fatty acid synthesis?

A

Acetyl CoA reacts with oxaloacetate to form citrate (CoA leaves). Citrate is carried out of the mitochondria. It’s then broken down into acetyl CoA and oxaloacetate by citrate lyase.

49
Q

How does oxaloacetate get back into the mitochondria after being used to transport acetyl CoA to the cytoplasm?

A

oxaloacetate is converted into malate by malate dehydrogenase (this turns NADH to NAD+) and then from malate to pyruvate by malic enzyme (this turns NADP to NADPH, the only other major way in the body to make NADPH than the pentose phosphate pathway). Pyruvate can be transported into the mitochondria.

50
Q

What does pyruvate carboxylase do?

A

Takes you from pyruvate to oxaloacetate

51
Q

What does pyruvate dehydrogenase do?

A

Takes you from pyruvate to acetyl CoA

52
Q

What are the steps of fatty acid synthesis?

A

So you have your acetyl CoA (from glucose usually).

  1. Acetyl CoA is turned into malonyl CoA (ATP to ADP) by acetyl CoA carboxylase. (irreversible step. committed step, no going back)
  2. Acetyl CoA binds to SH on the phosphantetheine (P group on ACP in fatty acyl synthase).
  3. Acetyl CoA moves to another SH linkage.
  4. Malonyl CoA binds to SH on the phosphantetheine of the acyl carrier protein (part of fatty acyl synthase).
  5. malonyl CoA attacks the acetyl CoA and joins up (releasing CO2)
  6. You’ve now got a chain of carbons, but it looks nothing like a fatty acid. NADPH reduces the carboxyl carbon-oxygen bonds, along with ketoreductase
  7. Dehydratase knocks off a water by forming a double bond on the alcohol-carbon.
  8. Enoyl reductase + NADPH reduce the double bond formed by dehydratase and you finally have an extended carbon chain.
  9. Rinse and repeat! This happens again and again, taking 2 NADPH for each malonyl CoA added (remember CO2 leaves so you only add 2 carbons each time) (also remember that the carbons are added to the “front”, what’s bound to ACP)
53
Q

Where does fatty acid synthesis get its NADPH from?

A

Pentose phosphate pathway (glucose 6 phosphate to ribulose 5 phosphate) and transport of oxaloacetate to the mitochondria (oxaloacetate –> pyruvate)

54
Q

Where does fatty acid synthesis get its carbon molecules from?

A

TCA cycle! (acetyl CoA, CO2 knocked off)

55
Q

Where does fatty acid synthesis get its energy from?

A

ATP from glycolysis and oxidative phosphorylation

56
Q

How do fatty acids form triacylglycerides after initial fatty acid synthesis?

A

Glycerol 3 phosphate + 3 fatty acids. In adipose tissue and the liver. glycerol 3 phosphate –> phosphatidic acid –> diacylglycerol –> triacylglycerol

57
Q

How are triacylglycerides transported through the body?

A

Packaged into very low density lipoproteins and transported to adipose cells for storage or muscles for use as energy.

58
Q

Where is long chain fatty acid synthesis done? How is it done?

A

In the endoplasmic reticulum, carried out by an oxidase that uses O2 and NADH. Catalyzed by enzymes: NADH-cytochrome b5 reductase, cytochrome b5, stearoyl CoA desaturase

59
Q

How is fatty acid synthesis regulated?

A

Fatty acid synthesis is maxed out when you have a ton of glucose and a ton of energy in the cellular environment. Rate limiting step is the committed step from acetyl CoA to malonyl CoA (acetyl CoA carboxylase +ATP). acetyl CoA carboxylase is positively regulated by citrate (you have finished TCA) and insulin. Acetyl CoA carboxylase is negatively regulated by palmitoyl CoA (a product of fatty acid synthesis).

60
Q

Describe hormonal regulation of fatty acid synthesis in the fed state

A

In the fed state you have a lot of insulin. Insulin activates a phosphatase which removes a phosphate from acetyl CoA carboxylase. The dephosphorylated acetyl CoA carboxylase is active and able to convert acetyl CoA to malonyl CoA.

61
Q

Describe hormonal regulation of fatty acid synthesis in the fasting state

A

When you’re fasting you have a lot of glucagon. Glucagon activates a protein kinase which phosphorylates and inhibits acetyl CoA carboxylase. Epinephrine and glucagon both induce fatty acid breakdown and inhibit fatty acid synthesis.

62
Q

What does fatty acid synthesis look like in cancerous cells?

A

Cancer increases fatty acid synthesis to produce more signaling molecules for growth. Enzymes for fatty acid synthesis are overexpressed in cancer cells. This is a potential target for killing cancer!

63
Q

What else are fatty acids used for?

A

Fatty acids are used to generate signaling molecules and membrane phospholipids.