L20: Lipid Metabolism I

Question 1

Explain the distribution and functions of lipids in the human body.

Answer 1

• Energy storage: triacylglycerols - Diffusion/electrical barriers: phospholipids, sphingolipids, plasmalogens, cholesterol - Protein modification: farnesol, myristic acid - Signal transduction: prostaglandins, thromboxanes - Digestion of food: bile acids

Question 2

Chemical structure and properties of FAs and triglycerides.

Answer 2

• FA = long alkyl chain ending in carboxyl group. Properties: hydrophobic alkyl chain, hydrophilic carboxyl group - Triacylglycerol = three FAs esterified to glycerol. Properties: hydrophobic

Question 3

What are essential FAs? Which are the essential FAs?

Answer 3

• These are FAs, which we are unable to synthesis. All other FAs needed in the body can be made from these. - Omega 3 (linolenic acid) and 6 (linoleic) are essential. Omega indicates distance of dbl bond from the end of alkyl chain.

Question 4

Significance of trans-FAs?

Answer 4

• Trans fatty acids cannot be broken down or made in our body. They accumulate and cause disease such as CVD. We can only make and use cis FAs.

Question 5

Explain how lipids are transported into the mitochondria. Is it in the form of TAGs or FAs?

Answer 5

• FAs are transported into the mitochondria.

Question 6

Compare the energy yield of beta-oxidation and glycolysis.

Answer 6

• Beta-oxidation of FAs vs glycolysis/oxphos/ETC of glucose yields much higher amounts of ATP. Order of 100+ to 36 ratio - Eg. 16 C FA = 8 acetyl-CoA (80 ATP), 7 NADH and 7 FADH (28 ATP total). Costs 2 ATP for formation of FA-CoA.

Question 7

Explain process of beta-oxidation. Include enzymes, substrates, cofactors and products.

Answer 7

Question 8

What is problematic about unsaturated and branched FAs in beta-oxidation? How are these handled?

Answer 8

• Unsaturated FAs: dbl bonds have to be moved around so enzymes used in beta-oxidation can recognize molecules and process them. a.) If dbl bond bw C3,4, isomerizes to trans-delta2-enoyl CoA b.) If dbl bond bw C4,5, reduced to trans-delta3-enoyl CoA, then isomerized to trans-delta2-enoyl CoA - Branched FAs: result from degradation of chlorophylls a.) requires peroxisomal alpha-oxidation, which starts with hydroxylation and ends with release of CO2

Question 9

What are the roles of peroxisomes?

Answer 9

• They perform alpha-oxidation of branched FAs - They perform beta-oxidation of long chain fatty acid chains preferentially. Here they produce hydrogen peroxide via an oxidase, instead of FADH.

Question 10

How does beta-oxidation differ in peroxisomes from other tissues?

Answer 10

• Beta-oxidation in peroxisomes involves preferential catabolism of LCFAs and produces hydrogen peroxide instead of FADH as seen in beta-oxidation in other tissue. Peroxisomes use oxidase enzyme

Question 11

Explain enzymatic defect leading to the development of acute fatty liver of pregnancy.

Answer 11

• Fetus releases hydroxyacyl metabolites into the mother’s circulation as a result of long chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency in the fetus. FAs accumulate in mother’s liver and they present with acute liver failure in pregnancy (jaundiced).

Question 12

What are disorders of FA degradation?

Answer 12

• Primary carnitine deficiency - Acyl-CoA dehydrogenase deficiency – eg. VLCAD, LCAD, MCAD and SCAD. MCAD is most common. - Refsum disease – alpha-oxidation deficiency - Peroxisome biogenesis disorders (PBD)

Question 13

How does carnitine deficiency present? What are the consequences?

Answer 13

• Without carnitine, FAs cannot be imported into mitochondria to be used as energy source. - Pts present as fasting non-ketotic hypoglycemia. Ketones are unusually low in blood or / and urine.

Question 14

What are features of FA degradation disorders?

Answer 14

• Ketone bodies are not produced as much.

Question 15

How does MCAD deficiency present? What are the consequences?

Answer 15

• MCAD = Medium chain acyl-CoA dehydrogenase. - Presents as non-ketotic hypoglycemia.

Question 16

How does alpha-oxidation defects present? What are the consequences?

Answer 16

• Phytanic acid (branched metabolite from chlorophyll) is not degraded during this disorder causing a disease known as Refsum disease, which is an accumulation of undegraded phytanic acid in blood and tissues caused by neurological defects.

Question 17

How do peroxisomal problems present? What are the consequences?

Answer 17

• Predominantly known as Zellweger Syndrome - This is inability to produce functional peroxisomes, which among other things, affects capacity to oxidize VLCFA. Diagnosis indicated by marked increased of 24 and 16 chain carbons (VLCFA and LCFAs in serum)

Question 18

Describe synthesis of ketone bodies

Answer 18

Question 19

Where are ketone bodies made? Where are ketone bodies used?

Answer 19

• Ketone bodies are made in both liver and kidney – mostly in liver. - Ketone bodies are used in any tissue other than the liver and kidney.

Question 20

Name the ketone bodies. How are they used?

Answer 20

• Ketone bodies: acetoacetate, acetone (result of spontaneous decarboxylation of acetoacetate) and beta-hydroxybutyrate. - Ketone bodies have the ability to cross membranes and can leave liver and travel to peripheral tissue. - Beta-hydroxybutyrate gets oxidized to acetoacetate via beta-hydroxybutyrate dehydrogenase (yields NADH) - CoA from succinyl-CoA is transferred to acetoacetate yielding acetoacetyl-CoA via enzyme acetoacetate:succinyl-CoA transferase - Thiolase produces 2 x acetyl-CoA from acetoacetyl-CoA, which function in the TCA cycle to produce energy. - Acetone cannot be converted to acetyl-CoA

Question 21

Why aren’t ketone bodies used in liver or kidney?

Answer 21

• These tissues don’t express acetoacetate:succinyl-CoA transferase to generate the intermediate: acetoacetyl-CoA that generates acetyl-CoA.

Question 22

During what environmental conditions are ketone bodies ordinarily formed?

Answer 22

• Ketone bodies are formed during starving times.

Question 23

What is the committed step in ketone body formation?

Answer 23

• Conversion of HMG-CoA to Acetoacetate via HMG-CoA lyase, which produces and acetyl-CoA. Procession through this step will commit the pathway to forming ketone bodies.

Question 24

How does NADH:NAD+ ratio determine predominant forms of ketone bodies in liver?

Answer 24

• If NAD+ concentration is low in liver/kidney, acetoacetate will be converted to beta-hydroxybutyrate, causing an increased concentration of NAD+ and decrease in NADH.

Question 25

Which intermediate during ketone body synthesis can function in another pathway (besides acetyl Co-A)? What pathway? During what environmental conditions will this occur?

Answer 25

• HMG-CoA = beta-hydroxy-beta-methylglutaryl-CoA - This molecule is used in the synthesis of cholesterol. - Will occur in well-fed times

Question 26

Why can type I diabetics have fruity breath? What is this a sign of?

Answer 26

• Fruity breath is an indicator of ketone body production (specifically aroma of acetone). This occurs when production of ketone bodies exceeds the use of ketone bodies. Ketosis is occurring and can lead to ketoacidosis.