Disorders of lipid metabolism

Question 1

fed state

Answer 1

increased insulin, decreased glucagon; causes fatty acid synthesis

Question 2

fasting state

Answer 2

decreased insulin, increased glucagon; causes fatty acid oxidation

Question 3

Fatty acid oxidation

Answer 3

1. ATGL catalyzes hydrolysis of first FA on triglyceride, trig becomes diacylglycerol.
2. Fatty acids are activated (CoA group attached) by ACS with the use of 2 ATP. Small and medium chain FAs can then diffuse freely into mitochondria. Long chain FAs need help from CAT1 to get across mitochondrial membrane. Very long chain FAs will travel to peroxisomes after activation, where they are shortened to medium/long.
3. Activated FAs in the mitochondria are converted into Acetyl-CoA by ACAD (beta oxidation)

Question 4

Where does the glycerol go after trig hydrolysis in FA oxidation?

Answer 4

glycerol goes to liver where it can be converted to glycerol 3P

Question 5

carnitine shuttle

Answer 5

Long chain FAs need help getting across the mitochondrial membrane. CAT1 enzyme brings them through the carnitine shuttle.

Question 6

beta oxidation

Answer 6

each turn of beta oxidation cycle shortens the FA by 2 carbons by generating one molecule of acetyl coA

Question 7

ACAD

Answer 7

enzyme that catalyzes the first reaction of b-oxidation in the mitochondria. Different isoforms for different chain length of FA. (eg MCAD, SCAD, LCAD)

Question 8

MCAD deficiency

Answer 8

defect in ACAD (MCAD) enzyme in FA oxidation, causes impaired ketogenesis, intolerance to prolonged fasting, hypoglycemia, coma, death

*possibly linked to SIDS, also causes similar symptoms to Reye’s syndrome

**ingestion of unripe Ackee fruit also acute MCAD deficiency because metabolism of the fruit blocks MCAD function

Question 9

chronic alcohol abuse

Answer 9

Individuals with alcohol abuse disorder commonly end up with fatty liver and over time consequent cirrhosis. That is not because ethanol blocks the MCAD enzyme but, the metabolism of ethanol requires large quantities of NAD+. NAD+ is also critical to the 3rd step of the beta-oxidation cycle. Thus, when NAD+ is in short supply, fatty acid oxidation is impaired and the liver begins to hold onto those unmetabolized fats. Because ethanol is a toxic substance, the body preferentially uses NAD+ for ethanol metabolism instead of fatty acid oxidation. Thus, chronic ethanol use impairs fatty acid metabolism.

Question 10

b-oxidation of even chain FAs

Answer 10

produces only Acetyl-CoAs; even chains are endogenously produced

Question 11

b-oxidation of odd chain FAs

Answer 11

produces Acetyl-CoAs and one molecule of propionyl-CoA (3 carbon).

Question 12

propionyl CoA metabolism

Answer 12

propionyl CoA —carboxylase +B7–> methylmalonyl CoA —mutase, B12—-> succinyl CoA.
*Succinyl coA can feed into TCA or gluconeogenesis.

Question 13

carboxylase enzyme defect

Answer 13

Deficiency in the carboxylase enzyme or vitamin b7 deficiency causes the build-up or retention of propionyl CoA which is an acidic compound. Can cause propionic acidura, also called propionic acidemia.

Question 14

methylmalonyl CoA mutase defect

Answer 14

if the enzyme methylmalonyl CoA mutase which catalyzes the second major step in the metabolism of propionyl CoA is defective or if there is a deficiency in vitamin B12, a critical cofactor for the mutase enzyme, then methylmalonyl levels will become elevated and a condition known as methylmalonic acidura or methylmalonic acidemia can occur.

Question 15

alpha hydroxylase

Answer 15

enzyme vital for breaking down branched long-chain FAs (like phytanic acid). First step in alpha oxidation. Deficiency here = Refsum’s disease

Question 16

omega oxidation

Answer 16

FA oxidation that starts at the omega carbon (opposite end) and occurs in the smooth ER primarily in kidney and liver cells. Produces succinate for TCA and waste product adipate which is excreted in urine. Upregulated when b-oxidation is blocked.

*Any elevation of adipate in the blood or urine is a principal sign of a disorder of fatty acid metabolism.

Question 17

Zellweger syndrome

Answer 17

absence of functional peroxisomes = inability to degrade very long chain fatty acids. Leads to abnormal liver, kidney, and muscle functions. Early death.

Question 18

ALD

Answer 18

mutated ACS enzymes in peroxisomes, causes demyelination

Question 19

Refsum’s

Answer 19

specific to alpha oxidation, the oxidation of long branch chain fatty acids. Mutation of alpha hydroxylase = buildup or retention of very long-chain branched fatty acids over time which impacts neuronal and muscle tissues. Symptoms: night blindness, ataxia, tremors, etc.

Question 20

ketone body metabolism

Answer 20

• promoted by prolonged FA oxidation, too much acetyl CoA in system so TCA cycle is overwhelmed. Body switches to using acetyl CoA for ketone body production.
• primarily produced in liver
• enzymes that synthesize ketones are in the mitochondria
• liver makes ketons but cannot use them - will secrete into blood stream.

*build up of ketones in blood can lead to ketoacidosis.

Question 21

Fatty acid biosynthesis

Answer 21

Acetyl CoA --> citrate (exits mitochondria via tricarboxylate transporter) --> converted back into Acetyl CoA by citrate lyase and ATP. 
Acetyl CoA (enzyme: ACC)--> Malonyl CoA --> FA synthesis by FA synthase adding additional malonyl CoAs to original Acetyl CoA until 16 carbon chain.

*elongases and desaturases introduce diversity

Question 22

ACC (Acetyl CoA Carboxylase)

Answer 22

enzyme that converts Acetyl CoA to malonyl CoA in FA synthesis

Question 23

FA synthase

Answer 23

enzyme that grows the FA by adding additional malonyl CoAs to original Acetyl CoA until 16 carbon chain

Question 24

essential fatty acids

Answer 24

linoleic and linolenic acids are essential because mammals do not have desaturase enzymes capable of introducing double bonds beyond carbon nine in the fatty acid chain (counting from the carboxylic end). Thus, complex poly-unsaturated fatty acids (PUFAs) like arachidonic acid, DHA and EPA could not be synthesized if we did not obtain the precursors linolenic and linoleic acid from the diet.