Explain the distribution and functions of lipids in the human body.
- Energy storage: triacylglycerols - Diffusion/electrical barriers: phospholipids, sphingolipids, plasmalogens, cholesterol - Protein modification: farnesol, myristic acid - Signal transduction: prostaglandins, thromboxanes - Digestion of food: bile acids
Chemical structure and properties of FAs and triglycerides.
- FA = long alkyl chain ending in carboxyl group. Properties: hydrophobic alkyl chain, hydrophilic carboxyl group - Triacylglycerol = three FAs esterified to glycerol. Properties: hydrophobic
What are essential FAs? Which are the essential FAs?
- 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.
Significance of trans-FAs?
- 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.
Explain how lipids are transported into the mitochondria. Is it in the form of TAGs or FAs?
- FAs are transported into the mitochondria.
Compare the energy yield of beta-oxidation and glycolysis.
- 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.
Explain process of beta-oxidation. Include enzymes, substrates, cofactors and products.
What is problematic about unsaturated and branched FAs in beta-oxidation? How are these handled?
- 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
What are the roles of peroxisomes?
- 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.
How does beta-oxidation differ in peroxisomes from other tissues?
- 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
Explain enzymatic defect leading to the development of acute fatty liver of pregnancy.
- 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).
What are disorders of FA degradation?
- 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)
How does carnitine deficiency present? What are the consequences?
- 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.
What are features of FA degradation disorders?
- Ketone bodies are not produced as much.
How does MCAD deficiency present? What are the consequences?
- MCAD = Medium chain acyl-CoA dehydrogenase. - Presents as non-ketotic hypoglycemia.
How does alpha-oxidation defects present? What are the consequences?
- 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.
How do peroxisomal problems present? What are the consequences?
- 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)
Describe synthesis of ketone bodies
Where are ketone bodies made? Where are ketone bodies used?
- 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.
Name the ketone bodies. How are they used?
- 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
Why aren’t ketone bodies used in liver or kidney?
- These tissues don’t express acetoacetate:succinyl-CoA transferase to generate the intermediate: acetoacetyl-CoA that generates acetyl-CoA.
During what environmental conditions are ketone bodies ordinarily formed?
- Ketone bodies are formed during starving times.
What is the committed step in ketone body formation?
- 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.
How does NADH:NAD+ ratio determine predominant forms of ketone bodies in liver?
- 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.
Which intermediate during ketone body synthesis can function in another pathway (besides acetyl Co-A)? What pathway? During what environmental conditions will this occur?
- HMG-CoA = beta-hydroxy-beta-methylglutaryl-CoA - This molecule is used in the synthesis of cholesterol. - Will occur in well-fed times
Why can type I diabetics have fruity breath? What is this a sign of?
- 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.