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Flashcards in Lipid synthesis and metabolism Deck (85)
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1

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

• 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?

2

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

• 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

3

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

• 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

4

what initiates the pathway of de novo lipogenesis?

• 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

5

Describe the overall process of Beta-oxidation

• 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

6

In what circumstances will beta oxidation occur?

• 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

7

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

• 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

8

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

• 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

9

Describe the overall pathway/process of ketogenesis

• 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

10

IN what situations does ketogenesis occur?

• 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

11

where in the cell does ketogenesis occur?

mitochondria

12

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

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

13

Describe the overall pathway/process of cholesterol synthesis

• 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

14

what is the most important reaction in cholesterol synthesis?

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

15

what is cholesterol used for in the cell?

• 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

16

You see ceramide backbone and you think…?

• 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

17

What are the three lipoprotein pathways?

• 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

18

What are the basic features of a fatty acid?

• 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

19

What is important about linoleic acid?

• 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

20

How can a fatty acid be named?

• 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

21

What are the three phases of fatty acid synthesis?

• 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

22

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

• 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

23

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

• 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

24

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

• 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

25

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

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

26

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

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)

27

what is the end product of fatty acid synthesis?

• 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

28

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

• 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

29

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

ER and mitochondria

30

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


• 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)