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Lipid synthesis and metabolism Flashcards

1
Q

What are the questions to be asking yourself when considering a metabolism pathway?

A

• Is the organism in a state of positive energy balance? (fed vs. fast)
• What tissue is under consideration? What does this tissue do for the body in terms of making macronutrients available?
○ GI tract, liver, skeletal muscle, adipose tissue
• What is the pathway?
○ Fatty acid synthesis
○ Fatty acid oxidation
○ Ketogenesis
○ Cholesterol synthesis
○ Phospholipid synthesis
○ Lipoprotein physiology
• Where in the cell is the pathway/reaction taking place
○ Plasma, cytoplasm, mitochondria, triglyceride storage pool, cell membrane
• What are the key steps in the pathway and what enzymes catalyze these steps
○ Transitions across membranes, energy consuming reactions, rate limiting steps
• How are the enzymes that catalyze the key steps regulated
○ Co facotrs, substrates or hormones?

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2
Q

Describe how acetyl coa is a hub for fatty acids and for glucose all in one

A

• Acetyl coa is the species added to pyruvate to form citrate in the first commited step of the TCA cycle
• Thus, it is part of the pathway that is either involved in glycolysis, gluconeogenesis, or, as it turns out, in fatty acid synthesis
• Acetyl coa can be made into HMG CoA
• HMG CoA is made into mevalonate, which is made into cholesterol
○ So acetyl CoA is in the cholesterol syntheisis pathway
• Actyle CoA can be made into malonyl Coa, which in turn is made into free fatty acids
• Fatty acids can be made into triglycerides OR phospholipids
• Triglycerides in turn can be broken down into fatty acids which will go back to acetyl CoA throug the intermediate of Acyl Carnitine
○ THUS ACETYL COA IS THE HUB OF LOTS OF LIPID HANDLING TO BE CONVERTED FROM GLUCOSE TO FAT THEN FROM FAT TO GLUCOSE

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3
Q

Describe the general process of fatty acid biosynthesis (de novo lipogenesis)

A

• When glucose is present in the liver or adipose tissue in excess
• Can go down glycolysis to pyruvate, enter mitochondria and be converted to acetyl CoA which can then be made into fatty acids
• To initiate this pathway, acetyl CoA must be converted to and leave the mitochondria as citrate, then be converted back to acetyl CoA in the cytoplasm
• It is then converted to malonyl coA in the rate limiting step catalyzed by acetyl CoA carboxylase
○ KEY ENZYME = acetyl CoA carboxylase
• Malonyl CoA is important as an intermediate because it inhibits the oxidation of fatty acids
• Units of acetyl CoA are put together 2 carbons at a time by the enzyme fatty acid synthase to form the growing fatty acid chain
○ This uses NADPH which is derived from the hexose monophosphate pathway
• Fatty acids can be packaged with glycerol into triglyceride which circulates in the blood as very low density lipoprotein VLDL triglyceride
• This VLDL can be taken up by adipose tissue through the action of lipoprotein lipase where it can be stored to be used when the body is in negative energy balance

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4
Q

what initiates the pathway of de novo lipogenesis?

A

• To initiate this pathway, acetyl CoA must be converted to and leave the mitochondria as citrate, then be converted back to acetyl CoA in the cytoplasm
• It is then converted to malonyl coA in the rate limiting step catalyzed by acetyl CoA carboxylase
○ KEY ENZYME = acetyl CoA carboxylase

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5
Q

Describe the overall process of Beta-oxidation

A

• Beta oxidation is the same thing as fatty acid oxidation
• When the body is in negative energy balance such as occurs during short term fasting or during exercise, fat becomes an important alternative fuel for muscle and liver
• This is in effor to preserve glucose availability for the brain
• Oxidation of fat during asting by the liver provides the energy (ATP) needed to fuel gluconeogenesis
○ Remember that the fatty acids do not contribute carbons, but they do contribute ATP
• When insulin is low and counter-regulatory hormones are high, triglyceride that has been stored in adipose tissue is broken down by the enzyme hormone sensitive lipase
○ KEY ENZYME = hormone sensitive lipase
• Fatty acids and glycerol released by this reaction enter the circulation and can be taken up by the liver where the fatty acid is used as an energy source through oxidation in the TCA cylce
• Glycerol serves as the substrate for gluconeogenesis
• A fatty acid that has entered the cytosol of a liver cell must gain access to the mitochondria to be oxidized
• To do this, the fatty acid must first be converted to an acyl carnitine which is then transported into the mitochondria by carnitine palmitoyl transferase 1
○ KEY ENZYME = carnitine palmitoyl transferase 1 = 1 CPT1
• This is rate limiting step in the apthway of fatty acid oxidation
• Once in the mitochondria, the fatty acyl CoA is regenerated and enters a series of reactions that sequentially remove 2 carbons at a time from the fatty acid as acetyle CoA which can then enter the TCA cycle leaving a fatty acyl CoA that is 2 carbons shorter
• This fatty acyl coA then enters another round of beta oxidation until it is chopped to peices

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6
Q

In what circumstances will beta oxidation occur?

A

• Beta oxidation is the same thing as fatty acid oxidation
• When the body is in negative energy balance such as occurs during short term fasting or during exercise, fat becomes an important alternative fuel for muscle and liver
• This is in effor to preserve glucose availability for the brain
• Oxidation of fat during fasting by the liver provides the energy (ATP) needed to fuel gluconeogenesis
○ Remember that the fatty acids do not contribute carbons, but they do contribute ATP
• When insulin is low and counter-regulatory hormones are high, triglyceride that has been stored in adipose tissue is broken down by the enzyme hormone sensitive lipase
KEY ENZYME = hormone sensitive lipase

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7
Q

What are the two bolded, important and regulated steps in the overall process of beta oxidation?

A

• When insulin is low and counter-regulatory hormones are high, triglyceride that has been stored in adipose tissue is broken down by the enzyme hormone sensitive lipase
○ KEY ENZYME = hormone sensitive lipase
• Fatty acids and glycerol released by this reaction enter the circulation and can be taken up by the liver where the fatty acid is used as an energy source through oxidation in the TCA cylce
• Glycerol serves as the substrate for gluconeogenesis
• A fatty acid that has entered the cytosol of a liver cell must gain access to the mitochondria to be oxidized
• To do this, the fatty acid must first be converted to an acyl carnitine which is then transported into the mitochondria by carnitine palmitoyl transferase 1
○ KEY ENZYME = carnitine palmitoyl transferase 1 = 1 CPT1

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8
Q

What is the rate limiting step and the key enzyme in the beta oxidation process of fatty acids?

A

• A fatty acid that has entered the cytosol of a liver cell must gain access to the mitochondria to be oxidized
• To do this, the fatty acid must first be converted to an acyl carnitine which is then transported into the mitochondria by carnitine palmitoyl transferase 1
○ KEY ENZYME = carnitine palmitoyl transferase 1 = 1 CPT1 (membrane crossing)
• This is rate limiting step in the pathway of fatty acid oxidation
• Once in the mitochondria, the fatty acyl CoA is regenerated and enters a series of reactions that sequentially remove 2 carbons at a time from the fatty acid as acetyle CoA which can then enter the TCA cycle leaving a fatty acyl CoA that is 2 carbons shorter
• This fatty acyl coA then enters another round of beta oxidation until it is chopped to pieces

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9
Q

Describe the overall pathway/process of ketogenesis

A

• Ketogenesis occurs in the mitochondria
• If insulin is very low or absent and counter-regulatory hormones are high
○ During long-term fasting, during a carbohydrate restricted ketogenic diet or in DKA
• In these circumstances the acetyl CoA produced by beta-oxidation in the liver can take an alternate route and become a “ketone body”
• Ketones = 3-hydroxy butyrate, and acetoacetate
• Ketones serve as an alternative fuel for the brain and other tissues in states of prolonged dietary glucose insufficiency
○ Fasting or low carb diets
• It is as though the body decides that continuing to break down muscle to provide substrate for gluconeogenesis is counter productive and the brain begins to use an alternate fuel that comes from fat to preserve lean body mass
• Common conditions where ketone body formation occurs
○ Starvation
○ DKA
○ Alcoholic ketoacidosis
• These conditions - very low insulin levles, high counter-regulatory hormones, an abundant source of substrate is present
○ Fatty acits or ethanol
• Ketones will only be formed when the acetyl CoA produced by fatty acid metabolism (or etoh metabolism) exceeds the capacity of the TCA cycle to metabolize it
○ ATP/ADP is high
• THE RATE LIMITING STEP IN KETOGENESIS = synthesis of hydroxyl methylglutaryl CoA
○ KEY ENZYME = HMG CoA synthase
• All this occurs in the mitochondria

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10
Q

IN what situations does ketogenesis occur?

A

• Common conditions where ketone body formation occurs
○ Starvation
○ DKA
○ Alcoholic ketoacidosis
• These conditions - very low insulin levles, high counter-regulatory hormones, an abundant source of substrate is present
○ Fatty acits or ethanol
• Ketones will only be formed when the acetyl CoA produced by fatty acid metabolism (or etoh metabolism) exceeds the capacity of the TCA cycle to metabolize it
○ ATP/ADP is high
• THE RATE LIMITING STEP IN KETOGENESIS = synthesis of hydroxyl methylglutaryl CoA
○ KEY ENZYME = HMG CoA synthase
• All this occurs in the mitochondria

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11
Q

where in the cell does ketogenesis occur?

A

mitochondria

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12
Q

what is the rate limiting step and key enzyme in ketogenesis?

A

• THE RATE LIMITING STEP IN KETOGENESIS = synthesis of hydroxyl methylglutaryl CoA
○ KEY ENZYME = HMG CoA synthase

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13
Q

Describe the overall pathway/process of cholesterol synthesis

A

• Cholesterol synthesis is important because cholesterol is part of the cell membrane, is a precursor for steroid hormones and bile acids, and also is the lipid that accumulates in atherosclerotic plaque
• Some cholesterol comes from the diet but it can be synthesized from acetyl CoA through the formation of hydroxymethyl glutaryl CoA
• THE RATE LIMITING STEP IN THIS PATHWAY is catalyzed by HMG-CoA reductase
• This reaction occurs in the cytosol and uses NADPH for energy
• Some important intermediates in this pathway are mevalonic acid
○ Precursor to geranyl phyprophosphate and farnesyl pyrophospate
○ These are intermediates in the cholesterol synthesis but can also be covalently attached to proteins to modulate function

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14
Q

what is the most important reaction in cholesterol synthesis?

A
  • THE RATE LIMITING STEP IN THIS PATHWAY is catalyzed by HMG-CoA reductase
    • This reaction occurs in the cytosol and uses NADPH for energy
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15
Q

what is cholesterol used for in the cell?

A
  • Cholesterol synthesis is important because cholesterol is part of the cell membrane, is a precursor for steroid hormones and bile acids, and also is the lipid that accumulates in atherosclerotic plaque
    • Some cholesterol comes from the diet but it can be synthesized from acetyl CoA through the formation of hydroxymethyl glutaryl CoA
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16
Q

You see ceramide backbone and you think…?

A
  • Sphingolipids!
    • Ceramide backbone is unique because it is derived in part from an amino acid (serine)
    • It contains a nitrogen atom
    • The glycosphingolipids also have a ceramide backbone but they have sugar residues attached to the head group
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17
Q

What are the three lipoprotein pathways?

A

• Dietary fat or chylomicron pathway
○ Triglyceride rich particles deliver dietary fat to skeletal muscle and adipose tissue
• BLDL pathway
○ Triglyceride derived form the liver is delivered to skeletal muscle and adipose tissue
• HDL pathway
○ Largely functions as a reservoir and transport system for a variety of lipids including cholesterol
○ HDL is though to be important in the transport of cholesterol from the periphery to the liver
○ Also though to be protective against atherosclerosis

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18
Q

What are the basic features of a fatty acid?

A
  • Hydrophobic hydrocarbon chain with a terminal carboxyl group
    • The terminal carboxyl group carries a negative charge at physiologic pH
    • They are amphipathic
    • Long chain - more hydrophobic, transported associated with proteins
    • Saturated - no double bond
    • Usually, addition of double bonds decreases the melting temperature of a fatty acid
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19
Q

What is important about linoleic acid?

A
  • Precursor of arachidonic acid that is a substrate for prostaglandin synthesis
    • Also, with linolenic acid are only obtained from diets
    • Human cells can’t make the double bonds in the proper places to form these de novo
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20
Q

How can a fatty acid be named?

A

• 20:4(5,8,11,14)
• 20 carbons in the chain, 4 double bonds at the 5 carbon and the 8 carbon…
• OR, alpha, beta, gamma (starting with second carbon in chain)
○ Last carbon is always omega carbon regardless of length
• Omega-3 fatty acid means start at the terminal carbon and go up three carbons to find the double bond

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21
Q

What are the three phases of fatty acid synthesis?

A
  • Production of cytosolic acetyl CoA
    • Conversion of acetyl CoA to malonyl CoA by acetyl CoA carboxylase
    • Conversion of malonyl CoA into palmitate by fatty acid synthetase
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22
Q

What is going on in the first phase of fatty acid synthesis?

A

• High levels of ATP will inhibit isocitrate dehydrogenase, leading to TCA cycle blocking and accumulaton of CITRATE
• Cytosolic acetyl CoA is from the mitochondria, and it is citrate (from acetyl CoA and OAA) that is transported from the mitochondria to the cytosol
○ Membrane transport is an important step
• Citrate in the cytosol is cleaved by ATP-citrate lyase that produces cytosolic acetyl CoA and OAA

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23
Q

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

A

• Conversion of acetyl coA to malonyl CoA by acetyl CoA carboxylase
• The energy for the carbon-to-carbon condensations in fatty acid synthesis is supplied by the process of carboxylation and then decarboxylation of acetyl gorups in the cytosol
• The carboxylation of acetyl CoA ot form malonyl CoA is catalyzed by acetyl CoA carboxylase
○ KEY ENZYME = acetyl CoA carboxylase
○ Requires HCO3 and ATP
• Biotin, which is covalently bound to a lysyl residue of the carboxylase serves as a coenzyme
• IMPORTANT, RATE LIMITING STEP - Carboxylation of acetyl CoA to form malonyl CoA is the rate limiting step for fatty acid synthesis
• Activation and deactivation of acetyl CoA carboxylase is the key event for regulation of fatty acid synthesis

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24
Q

what is going on in the third phase of fatty acid synthesis?

A

• Conversion of malonyl CoA into palmitate by fatty acid synthase
• Fatty acid synthase is a multifunctional, dimeric enzyme
• Seven different enzymatic activities plus a domain that covalently binds a molecule of 4’-phosphopanthetheine
○ This domain is ACP or acyl carrier protein because it carries acytyl and acyl units on its terminal thiol group
• There is a 4 step repeating cyle that adds 2 carbons per cycle to the fatty acid chain
○ All these reactions are catalyzed by fatty acid Synthase (FAS)
○ KEY ENZYME = FAS = FATTY ACID SYNTHASE
• Condensation to form 3-ketoacyl ACP
• Reduction of the keto group to alcohol
• Dehydration to introduce a double bond
• Reduction in the double bond to saturated bond
○ NADPH is used in the two reduction steps
• The hexose monophosphate pathway is the major supplier of NADPH for fatty acid synthesis
○ Also can use NADPH from cytosolic malate to pyruvate conversion (gluconeogenesis)
• The product of fatty acid synthesis is palmitic acid
• Palmitate is released from FAS by the palmitoyl thioesterase activity
First two carbons are from acetyl CoA and the rest are from malonyl CoA

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25
Q

What are the 4 reactions that are catalyzed by the behemoth of an enzyme FAS?

A

FAS = fatty acid synthase
• There is a 4 step repeating cyle that adds 2 carbons per cycle to the fatty acid chain
○ All these reactions are catalyzed by fatty acid Synthase (FAS)
○ KEY ENZYME = FAS = FATTY ACID SYNTHASE
• Condensation to form 3-ketoacyl ACP
• Reduction of the keto group to alcohol
• Dehydration to introduce a double bond
• Reduction in the double bond to saturated bond
○ NADPH is used in the two reduction steps
• The hexose monophosphate pathway is the major supplier of NADPH for fatty acid synthesis
○ Also can use NADPH from cytosolic malate to pyruvate conversion (gluconeogenesis)
• The product of fatty acid synthesis is palmitic acid
• Palmitate is released from FAS by the palmitoyl thioesterase activity
First two carbons are from acetyl CoA and the rest are from malonyl CoA

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26
Q

Where does the reduction energy in the FAS phase of fatty acid synthesis come from?

A

Reduction in the double bond to saturated bond
○ NADPH is used in the two reduction steps
• The hexose monophosphate pathway is the major supplier of NADPH for fatty acid synthesis
○ Also can use NADPH from cytosolic malate to pyruvate conversion (gluconeogenesis)

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27
Q

what is the end product of fatty acid synthesis?

A

• The product of fatty acid synthesis is palmitic acid
• Palmitate is released from FAS by the palmitoyl thioesterase activity
First two carbons are from acetyl CoA and the rest are from malonyl CoA

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28
Q

When you see omega-6 or omega-3 fatty acids you think…?

A
  • These can’t be generated by our bodies so they have to come from our diets
    • Carbon 9 and the omega end
    • Linoleic and linolenic acids
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29
Q

Palmitate can be converted to other long chain fatty acids by other enzymes. Where does this occur?

A

ER and mitochondria

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30
Q

What are the diet and metabolic conditions that regulate fatty acid synthesis?

A

• High carbohydrate leads to high pyruvate and acetyl CoA levels in the mitochondrion
• This favors production and translocation of citrate from the mitochondrion to the cytosol thus stimulating fatty acid synthesis
• High fat and low carbohydrate leads to low pyruvate flux into the mitochondrion
• Fat metabolism is associated with elevated acyl CoA in the cytoplasm and both conditions reduce fatty acid biosynthesis
• The hormonal enviroment:
○ High insulin favors lipogenesis (fatty acid biosyntehsis)
○ High glucagon favors lipolysis (beta-oxidation)

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31
Q

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

A
  • 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
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32
Q

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

A

• 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

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33
Q

How does citrate affect the function/action of ACC?

A

• 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

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34
Q

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

A

• 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

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35
Q

How does palmitoyl CoA affect the activity of ACC?

A
  • 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
Q

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

A
  • De-phosp = active, insulin, PP1

* Phosph = inactive, glucagon, PKA

37
Q

How do insulin and glucagon affect fatty acid synthesis?

A

• 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
Q

Describe what is going down in the synthesis of TAGs

A
  • 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
Q

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

A
  • 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
Q

How are TAGs stored?

A
  • 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
Q

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

A
  • 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
Q

What are the products of beta-oxidation?

A

• 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
Q

What are the three general stages of fatty acid degradation?

A
  • Release of fatty acid from TAG
    • Transport into the mitochondrial matrix
    • Repeated cycles of oxidation
44
Q

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

A

• 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
Q

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

A

• 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
Q

Why is CPT-1 a key enzyme?

A

• 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
Q

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

A
  • 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
Q

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

A

• 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
Q

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

A

• 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
Q

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

A
  • Step 2 - enoyl CoA hydratase

* Adds water across the trans double bond created in step 1

51
Q

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

A
  • Step 3 -Beta-hydroxy-CoA dehydrogenase

* Oxidizes the hydroxyl generating Beta-keto acyl-CoA and NADH from NAD

52
Q

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

A
  • Thiolase = step four

* Releases acetyl CoA and transfers the fatty acid shorted by two carbons to CoA-SH for another round

53
Q

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

A

• 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
Q

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

A

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
Q

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

A
  • 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
Q

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

A

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
Q

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

A

• 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
Q

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

A

• 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
Q

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

A

• 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
Q

What exactly ARE ‘ketone bodies’?

A
  • Acetoacetate (the progenitor that is either reduced with NADH or spontaneously decarboxylated)
    • 3-hydroxybutyrate
    • acetone
61
Q

Describe how the body uses ketone bodies (essentially, why does the body risk the ketoacidosis)?

A

• Acetoacetate and Beta-hydroxybutarate are water-soluble transportable forms of acetyl units
• The liver does not use ketone bodies itself as an energy source, bu tmany other tissues do
• In fact, they are the primary fuel choice for cardiac muscle and the renal cortex
• 3-hydroxybutarate is oxidized to acetoacetate by 3-hydroxy butyrate dehydrogenase, and this produces NADH
• Acetoacetate is then provided with a CoA taken from succinyl CoA by thiophorase
○ The product acetoacetyl CoA can be converted into two acetyl CoAs
• The liver does not have thiophorase
• So essentially the liver is generating these acyl groups that are easily transportable to give other tissues another source of acetyl CoA for the TCA cycle to continue

62
Q

What is the normal concentration of ketone bodies in the blood and in the urine of a normal person (as opposed to diabetic)?

A 
• Normal urinary secretion
		○ Less than 125 mg/24hr period
	• Diabetic urinary secretion
		○ Up to 5,000mg/24 hr period
	• Blood concentration normal
		○ Less than 3mg/100mL
	• Diabetic blood concentration
		○ 90mg/100mL
63
Q

What is the main enzyme that is super active in DKA?

A
  • Hormone sensitive lipase! We have essentially no insulin activity and tons of glucagon secretion and activity
    • Thus there is large amounts of fatty acid release from adipose
    • Fatty acid oxidation leads to high levels of NADH which inhibits the TCA cycle and forces excess acetyl CoA into the ketone body synthesis pathway
    • More ketone bodies in the blood (acetoacetate and 3-hydroxybutyrate) means acidosis
64
Q

In what two forms does cholesterol appear in the body?

A
  • Free cholesterol

* Cholesterol esters

65
Q

What are the sources of cholesterol?

A

• Dietary and de novo synthesis
• Dietary -
○ We consume about 600mg of cholesterol each day and 1/2 of which is absorbed
○ Meat, eggs, whole dairy products
○ Other half is stool excreted
• Synthesis -
○ We synthesize about 1g of cholesterol each day
○ Normally under tight regulation (mostly hepatocyte driven)
○ So we actually make more than we eat
○ The liver is the major site of cholesterol synthesis
○ Adrenal cortex, ovaries and testes also make cholesterol for steroid hormones
• Bile salts
○ About what we each each day is put into bile salts
○ Enterohepatic circulation keeps them in the body

66
Q

There are two isoforms of HMG CoA synthase in the hepatocyte. What do each of these isoforms do and where are they?

A
  • They are either in the cytoplasm or the mitochondria
    • Cytosolic isoform - cholesterol synthesis
    • Mitochondrial isoform - ketone body synthesis or ketogenesis
67
Q

Describe the three general steps in cholesterol biosynthesis

A

• First step -
○ Synthesis of HMG CoA from acetyl CoA
○ Similar to the synthesis of ketones and is catalyzed by thiolase and HMG CoA synthase
○ 2 isoforms of this enzyme in the hepatocyte
○ Cytosolic isoform participates in cholesterol synthesis
○ Mitochondrial version participates in ketone generation
• Second step -
○ Conversion of HMG CoA to mevalonate by HMG CoA reductase
○ RATE LIMITING STEP in the syntheiss pathway
○ KEY REGULATED STEP in the synthesis pathway
○ Cytosolic reaction and USES NADPH as the reducing agent
• Third “phase” -
○ Series of reactions to convert mevalonate to cholesterol
○ First converted to two activated isoprenes (isopentyl pyrophosphate)
○ Intermediat stage including geranyl phyrophosphate and farnesyl phyrophosphate
○ 2 molecules of farnesyl pyrophosphate combine to form squalene
○ Ring closure - squalene is turned into four-ring steroid structure, first as lanosterol then cholesterol

68
Q

There are 5 given things that are important to remember. What are these?

A
  • 1 - where the pathway occurs (cytoplasm)
    • 2 - synthesis STARTS with acetyl CoA
    • 3 - NADPH is the source of energy (reducing agent) for the synthetic pathway
    • 4 - the key regulated step is HMG-CoA reductase
    • 5 - the names of key intermediates (geranyl pyrophosphate, farnesyl pyrophosphate, isopentyl pyrophosphate, squalene, lanosterol)
69
Q

In what step of cholesterol synthesis is energy used?

A

• ATP is used (3) in the conversion of mevalonate into isopentenyl pyrophosphate
• NADPH (2) is used by HMG-CoA reductase in the conversion of HMG-CoA into mevalonate
*NADPH (2) is used in the reduction of squalene into the ring form of linosterol and cholesterol

70
Q

What “other fates” besides cholesterol synthesis are geranyl pyrophosphate and farnesyl pyrophosphate destined for?

A
  • Prenylated proteins
    • Heme a
    • Dolichol
    • ubiquinone
71
Q

What three pathways contribute to the intracellular cholesterol content in hepatocytes

A

• Intracellular synthesis
• Uptake of lipoprotein cholesterol from LDL and to a lesser extent HDL particles
• Enterohepatic circulation of bile acids
○ Bile acids are made up by cholesterol, are secreted and are taken back up in the small intestine (distal ileum)

72
Q

The key regulated step in cholesterol synthesis is what? And what are the regulating molecules/processes?

A
  • HMG CoA reductase is the key regulated enzyme and the key regulated step in cholesterol biosynthesis (de novo)
    • Transcriptional regulation
    • Translational regulation
    • Degradation of key enzyme
    • Phosphorylation of key enzyme
73
Q

Describe the transcriptional regulation of cholesterol synthesis

A

• When cholesterol is present in excess, HMG-CoA reductase gene is transcribed at a dramatically reduced rate
• Transcriptional control is the result of the actions of the transcription factor Sterol Regulatory Element Binding Protein
○ SREBP - super important to recognize
• When cholesterol levels are high in the hepatocyte, SREBP is retained in the golgi through binding to another protein, SCAP
• In this situation there is no stimulation of HMG-CoA reductase transcription
• When cholesterol levels are high, SREBP is released and can move to the nucleus to stimulate transcription of HMG-CoA reductase
• Insulin and glucagon regulate HMG-CoA reductase via transcription
• Insulin increases the expression of this enzyme
○ NADPH is high and acetyl CoA is present for the start of the synthesis pathway
• Glucagon decreases expression

74
Q

How do statins work in general?

A

• They are analogs to mevalonate and thus competitively interfere with HMG-CoA reductase function
• Essentially a statin will drastically reduce or shut off the de novo synthesis of cholesterol
• Since we have about 1g of de novo synthesis, and about 1/2 that dietary intake, this goes a long way to lowering cholesterol in the body
○ Successful medication in preventing coronary artery disease CAD

75
Q

Describe how the phosphorylation state of HMG-CoA reductase contributes to regulation of this key enzyme in the biosynthesis of cholesterol

A
  • AMP kinase phosphorylates HMG-CoA reductase which inactivates the enzyme
    • Phosph - deactive
    • Dephosph - active
76
Q

Describe the regulation of HMG-CoA reductase at the level of protein degradation

A

• When cholesterol is present in excess in the hepatocyte, the 1/2 life of HMG-CoA reductase decreases from 11 hrs to 2 hours
○ Targeted to the proteosome

77
Q

Describe the translational regulation of HMG-CoA reductase

A
  • When cholesterol is present in excess, the translation rate of the mRNA encoding HMG-CoA reductase is much less than in the absence of cholesterol
    • The mRNA half-life decreases with excess cholesterol
78
Q

What is meant by “complex lipids”?

A

• The varied and diverse class of lipids that have all sorts of diverse functions and relatively complex structures
• Know these well enough to know what buckets they fall in and associate them with key functions
• Triacylglycerols
○ Neutral storage lipids
• Phospholipids
○ Glycerophospholipids
○ Sphingolipids
§ Ceramide
• Glycolipids
○ Sphingosine backbone with a mono or oligosaccharide attached to it

79
Q

Describe the general architecture of the lipid

A

• Backbone of either glycerol or ceremide
• Polar head group either a phosphate linked to alcohol
○ Glycerophospholipid
• Or phosphate linked to choline
○ Sphyngomyelin
• Or phosphate linked to a sugar moiety
○ glycosphyngolipid

80
Q

What are the important things to remember about phosphatidylcholine?

A
  • Along with PE, it is the most abundant phospholipid in the body
    • Main component of lung surfactant
    • Serves as a reservoir of choline
    • Present in bile acids
81
Q

What is the importance of phosphatidylserine?

A
  • Also important for membrane synthesis

* Mostly synthesized by base exchange reaction

82
Q

What are the important points of phosphatidylinositol?

A

• Important in signal transduction
○ IP3 and DAG and calcium release into the cell from ER stores
• Serves as a reservoir for arachidonic acid which is used in prostaglandin synthesis
• Important in membrane protein anchoring

83
Q

What are the important points of sphingomyelin?

A

• Has a sphingosine/ceramide backbone
○ Not glycerol
• Has a choline headgroup
• Major structural lipid in NERVE tissue
• Precursor to this lipid is ceramide made from a fatty acid and an amino acid
○ serine

84
Q

What are important things to remember in glycolipids or glycosphingolipids

A

• They have a ceramide or sphingosine backbone
○ Instead of phosphate + alcohol head group though they have a sugar headgroup
• UDP glucose or UDP galactose are the sugars added to the head groups
• Most important examples
○ Cerebroside
○ Globoside
○ Gangliosides
• Breakdown disorders here are classic STEP questions and can lead to multisystem problems

85
Q

What, concerning prostaglandins and leukotrienes, are important to remember?

A

• INFLAMMATION
• These lipids are synthesized from the dietary fat linoleic acid
○ Converted to arachadonic acid and then to prostaglandin by COX
• Arachadonic acid can also be converted to leukotrienes via 5-lipoxygenase
• Prostaglandins are important in fever generation and inflammation
• COX inhibitors are used clinically as anti-inflammatory agents
• Leukotrienes are also important in inflammation and inhibitors of 5-lipoxygenase are used in asthma treatment

DEMS (30 decks)

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