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Flashcards in Lipid synthesis and metabolism Deck (85)
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31

What is happening in a diet that is consistently in excess calories?

• Increased transcriptional expression of acetyl CoA carboxylase and fatty acid synthase
• Fasting, however, casues a reduction of expression in these two proteins/enzymes
• Essentially the body is paving the way for less or more fatty acid synthesis depending on constant fed or fast conditions

32

What is the key, rate limiting step in fatty acid synthesis? What three species are the regulatory signals?

• Key step here is the conversion of acetyl CoA to manonyl CoA
• Through acetyl CoA carboxylase = ACC
• The three species that regulate this conversion
○ Citrate, fatty acid CoA and hormones

33

How does citrate affect the function/action of ACC?

• Citrate can activate ACC by causing polymerization of the enzyme and by increasing the Vmax
• Availability of cytosolic citrate determines the amount of acetyl CoA available for fatty acid synthesis
○ It also helps produce NADPH for the reducing equivalents used in the reactions

34

What is the interplay of glycolysis and fatty acid synthesis at the level of cytosolic production of pyruvate?

• Remember that OAA is converted to malate to be decarboxylated into pyruvate
• The decarboxylation of malate into pyruvate CHARGES an NADPH molecule
○ Meaning it takes an NADP to make this happen
• This NADPH molecule is the reducing equivalent needed for the conversion of acetyl CoA to palmitate for fatty acid synthesis
• Also remember that the acetyl CoA came from citrate, which exited the mitochondria to the cytoplsam to be cleaved to acyteyl CoA

35

How does palmitoyl CoA affect the activity of ACC?

• ACC = acetyl coA carboxylase
• This is the enzyme that makes palmitate
• The long chain fatty acid palmitoyl CoA will depolymerize ACC and thus inhibit activity
• This is feedback inhibition
• Cytosolic levels of long chain fatty acid are elevated during starvation or on high fat diets

36

What does the phosphorylation state of ACC have to do with its activity?

• De-phosp = active, insulin, PP1
• Phosph = inactive, glucagon, PKA

37

How do insulin and glucagon affect fatty acid synthesis?

• Insullin promotes fatty acid synthesis indirectly
○ Promoting glucose utilization and increased pyruvate flux
○ Also, insulin can activate protein phosphatase which dephosphorylates ACC and activates the enzyme
○ Remember that phosphorylation of ACC is deactivation
• Glucagon increases intracellular cAMP leading to active PKA which phosphorylates and inhibits ACC

38

Describe what is going down in the synthesis of TAGs

• TAGs = triacylglycerides
• The fatty acids produced by fatty acid synthase are stored as triacylglycerols (TAGs)
• Glycerol phosphate is the initial acceptor of fatty acid CoAs during TAG synthesis
• Two fatty acids are sequentially added, then the phosphate group is removed prior to the addition of the third fatty acid
• The three fatty acids esterified to a glycerol molecule are usually not of the same type
• Fatty acid on carbon one is saturated
• Carbon 2 fatty acid is unsaturated
• Carbon 3 is either saturated or unsaturated

39

What are the two ways to produce glycerol phosphate and in what tissues are these pathways used?

• Glycerol phosphate can be produced through glycolysis or directly by phosphorylation of glycerol
• Only the liver can do both pathways
• Adipose tissue must get to dihydroxyacetone phosphate through glycolysis to get glycerol phosphate
• KEY ENZYME = glycerol-P-dehydrogenase

40

How are TAGs stored?

• They are stored in the adipocytes
• They get there by being packaged in the liver with cholesterol, phospholipids and apoB-100 into VLDL particles
• These VLDL particles are secreted into the blood to get to the adipocytes
• These are the major energy reserve of the body

41

How does fatty acid synthesis lead potentially to fatty liver disease?

• General - chronic alcoholism causes hyperlipidemia in both the liver and the serum
• Ethanol is oxidized to acetate, primarily in the liver
• The increased NADH will slow the TCA cycle and fatty acid oxidation, which promotes the use of NADH to form glycerol-3-P
• It is glycerol-3-P that allows for the addition of fatty acids to become triacylglycerols
• The liver secretes abnormally high levels of VLDLs in this condition, but in the later stages of liver dysfunction there is less protein production
• Thus, the TAGs can't be packaged into the VLDL protein rich particles and are instead just hanging around in the liver, causing fatty liver disease

42

What are the products of beta-oxidation?

• NADH and FADH2 and Acetyl CoA
• NADH and FADH2 can be oxidized by the electron transport chain reactions to yield 3 ATP (NADH) and 2 ATP (FADH2)
• Acetyl CoA enters into the TCA cycle and converts into CO2 and H20
○ Each acetyl CoA can yield 12ATP
• 9 kcal/g of fat (opposed to 4kcal/g of protein or carbohydrate)

43

What are the three general stages of fatty acid degradation?

• Release of fatty acid from TAG
• Transport into the mitochondrial matrix
• Repeated cycles of oxidation

44

What is going on in the first general stage of fatty acid degradation?

• Release of fatty acid from the storage form of TAG
• This process is initiated by hormone sensitive lipase
• KEY ENZYME = hormone sensitive lipase
• KEY REGULATION PARADIGM = hormone signaling leading to cAMP levels and either dephosphorylation or phosphorylation of HSL
○ Phosph = active
○ Dephosph = inactive
• This enzyme removes a fatty acid from carbon 1 and/or 3 of the TAG (just not the middle one)
• HSL is active when it is phosphorylated by a cAMP-dependent protein kinase
○ Thus, under situations of low insulin, high glucagon
• In adipocytes, epinephrin is the primary counter-regulatory hormone that stimulates the increased cAMP levels

45

What is going on in the second general phase of fatty acid degradation?

• Transport of fatty acids into the mitochondrial matrix
• There has already been the work of HSL that has freed the fatty acids from the TAG storage molecule, now these free fatty acids need to get where they enter the TCA cycle and eventually give ATP through oxidative phosphorylation
• Fatty acids are converted into their CoA derivatives in the cytosol
• Acyl-CoA molecules cannot enter the mitochondrial matrix so the long-chain acyl group is transferred to carnitine
○ KEY ENZYME = CPT-1 = carnitine-palmitoyl transferase-1
○ Inhibited by malonyl CoA so that newly made palmitate isn't immediately shunted to mitochondria for degradation
• Remembet that medium or shorter fatty acids chains can get into mitochondria on their own

46

Why is CPT-1 a key enzyme?

• Acyl-CoA molecules cannot enter the mitochondrial matrix so the long-chain acyl group is transferred to carnitine
○ KEY ENZYME = CPT-1 = carnitine-palmitoyl transferase-1
○ Inhibited by malonyl CoA so that newly made palmitate isn't immediately shunted to mitochondria for degradation
• Remembet that medium or shorter fatty acids chains can get into mitochondria on their own

47

What's going on in the third general phase of fatty acid degradation?

• Beta oxidation, in which the beta carbon of the chain is oxidized, is the major pathway of fatty acid oxidation
• Each cycle has 4 steps and results In the production of one acetyl CoA, one FADH2 and one NADH
• Step 1 = 1 acyl CoA dehydrogenase
• Step 2 = enoyl CoA hydratase
• Step 3 - Beta-hydroxy-CoA dehydrogenase
• Step 4 - thiolase

48

what is Step 1 of the beta oxidation 4-step cycle?

• Step 1 = 1 acyl CoA dehydrogenase
• Step 1 -
○ Located in mitochondrial matrix
○ Oxidizes acyl CoAs
○ Four forms of the eznyme exist specific for short, medium or long carbon chains
○ The enzyme uses FAD and introduces a TRANS double bond
○ Genetic defects in all four enzymes have been described, resulting in severe hypoglycemia provoked by fasting
○ Medium chain fatty acyl CoA dehydrogenase (MCAD) deficiency has been identified as the cause of some cases of sudden infant death syndrome, likely because infants rely on milk for nutrition and milk contains mostly medium chain fatty acids

49

Some forms of sudden infant death syndrome can be traced back to a problem in what step of beta oxidation?

• Step 1 = 1 acyl CoA dehydrogenase

*○ Medium chain fatty acyl CoA dehydrogenase (MCAD) deficiency has been identified as the cause of some cases of sudden infant death syndrome, likely because infants rely on milk for nutrition and milk contains mostly medium chain fatty acids

• Step 1 -
○ Located in mitochondrial matrix
○ Oxidizes acyl CoAs
○ Four forms of the eznyme exist specific for short, medium or long carbon chains
○ The enzyme uses FAD and introduces a TRANS double bond
○ Genetic defects in all four enzymes have been described, resulting in severe hypoglycemia provoked by fasting

50

What is step 2 of the 4-step beta-oxidation cycle?

• Step 2 - enoyl CoA hydratase
• Adds water across the trans double bond created in step 1

51

What is step 3 of the 4-step beta-oxidation cycle?

• Step 3 -Beta-hydroxy-CoA dehydrogenase
• Oxidizes the hydroxyl generating Beta-keto acyl-CoA and NADH from NAD

52

What is step 4 of the 4-step beta oxidation cycle?

• Thiolase = step four
• Releases acetyl CoA and transfers the fatty acid shorted by two carbons to CoA-SH for another round

53

What about all the odd-carbon fatty acids? Or the ones with double bonds or SUPER long chains?

• Odd-chain length fatty acids are rare in the diet
• They are oxidized by beta oxidation until there is a 3-carbon proprionyl CoA that remains
• In 3 steps this proprionyl CoA is converted to succinyl CoA, which is an intermediate in the TCA cycle
• The conversion of propionyl CoA to succinyl CoA uses biotin and vitamin B12
• Oxidation of monounsatruated fatty acids like oleic acid requires an additional enzyme
○ 3,2-enoyl CoA isomerase
○ This will convert the weird double bond architecture back to the template for hydratase so beta oxidation can continue
• If there is a POLYunsaturated fatty acid, This requires an NADPH-dependent reductase in ADDITION to the isomerase
*SUPER long chains are broken down in the peroxisome and that is important for neutrophil function

54

What vitamin/mineral deficiencies would directly mess with the handling of odd-carbon fatty acids?

biotin or vitamin B12
• In 3 steps this proprionyl CoA is converted to succinyl CoA, which is an intermediate in the TCA cycle
• The conversion of propionyl CoA to succinyl CoA uses biotin and vitamin B12

55

What might happen in terms of beta oxidation products in a patient with a vitamin B12 deficiency?

• Both propionate and methylmalonate are excreted in the urine
• If either the mutase is missing or they are unable to use B12 as a co-facotr there is methylmalonic acidemia and aciduria
• The end result here is lactic acidosis

56

what is the general, end result of a problem in beta-oxidation?

The body relies too much on glucose, and since beta-oxidation is the main way in which a fasting state body can produce glucose (the energy necessary to fuel gluconeogenesis) then there is dangerously low hypoglycemia in these patients in a fasting state

57

What conditions would lead to the accumulation of acetyl CoA and thus favor the synthesis of ketone bodies?

• During fatty acid oxidaiton, elevated hepatic acetyl CoA and NADH inhibit pyruvate dehydrogenase
• BUT these same conditions activate pyruvate carboxylase and the OAA thus produced is used for gluconeogenesis rather than TCA cycle
• Also, high levels of NADH during fatty acid oxidation will inhibit the TCA cycle enzymes
○ Isocitrate dehydrogenase
○ Alpha-ketoglutarate dehydrogenase complex
• Inhibition of TCA cycle results in accumulation of acetyl CoA and thus favors ketone bodies synthesis

58

What is the first synthetic step of ketogenesis and what happens in this step?

• First synthetic step = formation of acetoacetyl CoA
• Occurs by reversal of the thiolase reaction of fatty acid oxidation
• Next, mitochondrial HMG CoA synthase combines a third molecule of acetyl CoA with acetoacetyl CoA to produce HMG CoA
• RATE LIMITING STEP = production of HMG CoA
○ Catalyzed by KEY ENZYME - HMG CoA synthase

59

What is the first synthetic step of ketogenesis and what happens in this step?

• First synthetic step = formation of acetoacetyl CoA
• Occurs by reversal of the thiolase reaction of fatty acid oxidation
• Next, mitochondrial HMG CoA synthase combines a third molecule of acetyl CoA with acetoacetyl CoA to produce HMG CoA
• RATE LIMITING STEP = production of HMG CoA
○ Catalyzed by KEY ENZYME - HMG CoA synthase
• HMG CoA is cleaved to produce acetoacetate and acetyl CoA by HMG CoA lyase
• Acetoacetate can be reduced to form 3-hydroxybutyrate with NADH
• High levels of NADH produced during fatty acid oxidation favors the conversion of acetoacetate to 3-hydroxybutrate
• Acetoacetate can also spontaneously decarboxylate to form acetone
• Acetoacetate, 3-hydroxybutyrate and acetone are collectively called the KETONE BODIES

60

What exactly ARE 'ketone bodies'?

• Acetoacetate (the progenitor that is either reduced with NADH or spontaneously decarboxylated)
• 3-hydroxybutyrate
• acetone