Metabolism Cases II

Question 1

Major Pathway that Supply Blood Glucose
v.
Major Pathway that Supply Fuel
During Fed State

Answer 1

Blood Glucose: Dietary Carbohydrates

Energy Homeostasis/ATP Production: Glycolysis, TCA, ETC

Question 2

Major Pathway that Supply Blood Glucose
v.
Major Pathway that Supply Fuel
During Short term Fasting State (5-16hrs)

Answer 2

Blood Glucose: Liver Glycogenolysis (100g, primary source), secondary = gluconeogenesis
Energy Homeostasis/ATP Production: Fatty Acid Oxidation & TCA/ETC
(Except for Brain Which uses Glucose!) (all other tissues use fatty acids at this stage)

Question 3

Major Pathway that Supply Blood Glucose
v.
Major Pathway that Supply Fuel
During Short Fasting State (16-24hrs)

Answer 3

Blood Glucose: Primarily Liver Gluconeogenesis, and now liver glycogenolysis is secondary
Energy Homeostasis/ATP Production: Fatty Acid Oxidation & TCA/ETC cycle, and now also a little Ketone Oxidation
((Except for Brain Which uses Glucose!) (all other tissues use fatty acids at this stage)

Question 4

Major Pathway that Supply Blood Glucose
v.
Major Pathway that Supply Fuel
During Long Terrm Fasting State (>24hrs)

Answer 4

Blood Glucose: Gluconeogensis (~130g/day; 50% hepatic and 50% renal)
Energy Homeostasis/ATP Production: Fatty Acid Oxidation & TCA/ETC and now also a lot of KETONE OXIDATION
(Fuel moleucles which provide enegy (ATP)
Muscle: fatty acids/ketone bodies
Adipose and Liver: Fatty Acids
Brain: Ketone Bodies/Glucose

Question 5

Major Pathway that Supply Blood Glucose
v.
Major Pathway that Supply Fuel
During Long Term Fasting (>2days)

Answer 5

Blood Glucose: Gluconeogensis (~130g/day; 50% hepatic and 50% renal)
Energy Homeostasis/ATP Production: Fatty Acid Oxidation & TCA/ETC and now also a lot of KETONE OXIDATION
(Fuel moleucles which provide enegy (ATP)
Muscle: fatty acids/ketone bodies
Adipose and Liver: Fatty Acids
Brain: Ketone Bodies/Glucose

Question 6

What is the role of carnitine in fatty acid metabolism and the normal role of fatty acid metabolism in the fasting state?

Answer 6

• Carnitine is needed to transport long‐chain fatty acids across the inner mitochondrial membrane (the carnitine shuttle).
• Normally, fatty acid catabolism via β‐oxidation in the mitochondria will account for the vast majority of energy production in most tissues of the body during fasting

Question 7

What is the rate-limiting enzyme of Lipolysis. What is the mechanism of enzyme in a health individual and activation of pathway is a patient with carnitine deficiency?

Answer 7

Rate limiting enzyme: Hormone Sensitive Lipase
Activation: HSL is activated by high EPINEPHRINE and LOW insulin (makes sense that you want to free fatty acids during fasting)
Inhbition: HSL is inhibited by HIGH Insulin and low epinephine (makes sense you want to save your stored FA in adipocytes)
carnitine deficiency effect: the Hypoglycemia in the effected patient will result in low insulin, exacerbating the situation by increasing the activity of HSL and mobilizing more free FA, which then can’t be oxidized and they build up in blood.

Question 8

What is the rate-limiting enzyme of Fatty Acid Oxidation. What is the mechanism of enzyme in a health individual and activation of pathway is a patient with carnitine deficiency?

Answer 8

Rate limiting enzyme: Carnitine palmitoyl transferase I (CPTI)
Activation: CPTI is active in the absence of malonyl CoA (which would be present during FA synthesis during fasting state, because citrate spill out into the cytoplasm, made into OAA and AcCoA(cyto) via ATP citrate lyase. Then the AcCoA is made into malonyl CoA via the rate limiting enzyme of FA synthesis: AcCoA Carboxylase (adding CO2 to AcCoA)
Inhbition: CPTI is inhibited by malonyl CoA, (check above) malonyl CoA levels are enhanced by insulin
carnitine deficiency effect: because of the deficient carnitine, CPTI will be much less active

Question 9

Why does hypoglycemia develop in a patient with carnitine deficiency after a 10 hour fast?

Answer 9

There are three main factors:
1) Failure of gluconeogenesis.
-Because there is no β‐oxidation of fatty acids, there is no ATP to power gluconeogenesis
2) Glycogenolysis is accelerated
-No gluconeogenesis means liver glycogen is much more rapidly depleted (hypoglycemia develops in ~10 hours)
3) In the absence of β‐oxidation, glucose metabolism is accelerated to fill the void. Muscle
will also use glucose under these conditions: e.g., AMPK will promote the translocation
of GLUT4.

Question 10

Liver biopsy of a patient with carnitine deficiency revealed that the patient’s hepatomegaly is due to a fatty liver. What is causing the fatty liver in this patient?

Answer 10

Carnitine deficiency (and resulting decrease in β‐oxidation) causes fatty acids to accumulate in
the liver (and muscle)
-Hypoglycemia leads to excessive lipolysis in the adipose tissue, mobilizing large
quantities of free fatty acids
-The liver will normally reassemble ‘excess’ FFAs into TAG for export as VLDL (repackaging). However, with little β‐oxidation occurring, the volume of FFAs and TAG for repackaging exceeds the norm and the TAG accumulates in the hepatocytes.

Question 11

Why is the concentration of serum ketone bodies low in a patient with carnitine deficiency?

Answer 11

-Normally, ketogenesis is regulated in part by shunting acetyl CoA, which accumulates
from β‐oxidation of fatty acids, into ketogenesis.
-The lack of β‐oxidation of fatty acids means there is no accumulating acetyl CoA.

Question 12

Explain how the profound hypoglycemia (18 mg/dL) exacerbates the muscle weakness

Answer 12

-In fasting, fatty acids are the predominate fuel for muscle. Diminished fatty acid
oxidation means less ATP which will lead to muscle weakness
-Low glucose means there is no “backup” for ATP production
-Hypoglycemia results in very low insulin levels which will accelerate muscle protein
degradation which will also contribute to muscle weakness and loss of tone

Question 13

Explain how the profound hypoglycemia (18 mg/dL) increases the level of blood ammonia (hyperammonemia) and decreases the production of urea (BUN; blood urea nitrogen)

Answer 13

-Amino acid catabolism is accelerated due to very
low insulin levels, as well as a lack of other fuels
(fatty acids and glucose)
-High amino acid catabolism generates the need to
dispose of the nitrogen as the carbon skeletons of
amino acids try to enter gluconeogenesis
o The urea cycle and glutamine synthetase
(upcoming lecture & workshop) are two
mechanisms for nitrogen disposal
o Both mechanisms require ATP
-This will lead to a decline in ammonia clearance
from blood.

Question 14

The coma in this patient with carnitine deficiency is due to hypoglycemia, as well as the hyperammonemia. What effect will hypoglycemia have on the brain? Recall that GLUT1 and GLUT3 are the primary brain glucose transporters, each with a very low km.

Answer 14

-When blood glucose falls below 20 mg/dL, coma will develop within several minutes
-Glucose transporters are no longer saturated and brain hexokinase is no longer functioning
at Vmax
-Resulting low G‐6‐P will rapidly result in insuffiient ATP production for brain cellular need

Question 15

LPL deficiency can be caused by inherited defect in lipoprotein lipase (LPL) or apolipoprotein CII. LPL is anchored onto the vascular endothelial lining via heparan sulfate chains of the endothelial cell glycocalyx. Why is IV heparin administered to these patients before running enzyme tests for LPL?

Answer 15

-Normally, LPL is not circulating, but is instead firmly attached to the glycocalyx of the
endothelia.
-Administration of IV heparin (a soluble glycosaminoglycan), will result in the release of
LPL from the glycocalyx as LPL will bind to circulating heparin instead.
-When blood is drawn for testing, LPL will then be present in the serum sample.
-A patient with impaired LPL activity would have a decrease in measurable LPL activity.

Question 16

A patient was brought to the hospital at 8:00 am, 14 hours after his last meal which had an extremely high fat content. On arrival a blood specimen was drawn. Within 15 minutes the laboratory technician reported that valid results could not be obtained from the blood plasma because it was loaded with fat. The plasma was milky but on centrifugation for 30 min at 15,000 rpm, it became clear, and there was a thick creamy top layer located on the specimen. What type of hyperlipidemia do you suspect in this patient. Why?

Answer 16

-Creamy band on top of the serum after centrifugation indicates elevated CM and suggests
hyperchylomicronemia.
-Timing of illness after a fatty meal also suggests the lipoproteins are of intestinal origin (again, CM)
-Normally, CM are removed from circulation within 4‐6 hours after a meal, so their presence in the plasma after 14 hours of fasting is grossly
abnormal. -TAG should be grossly elevated
-Cholesterol should be near normal

Question 17

What are the reasons for weight loss on a high protein / high fat and very low carb diet?

Answer 17

-Observant dieters can maintain low blood glucose, low I/G ratio:
~Liver glycogen is quickly depleted and incompletely replaced: weight of the amylopectin and associated water (early stage).
~Low insulin will activate hormone‐sensitive lipase, increasing mobilization of TAG and oxidation of fatty acids (depending on degree of dietary fat consumption).
~Gluconeogenesis accelerates to maintain blood glucose levels, and increased amino acid catabolism can increase urea cycle activity, both energy‐consuming processes.
-Proteins and fats slow gastric emptying and are thus more satiating; also, amino acids, particularly
leucine, act to trigger satiety in the brain. This may lead to lower food consumption (fewer calories)
overall.
-Enhanced thermogenic effect as protein requires more energy for digestion, absorption, and
catabolism.

Question 18

What would you predict the cholesterol and triacylglycerol levels of a person with LPL deficiency?

Answer 18

-Normally, CM are removed from circulation within 4‐6 hours after a meal, so their presence in the plasma after 14 hours of fasting is grossly
abnormal
-TAG should be grossly elevated
-Cholesterol should be near normal
Note: It is not known why VLDLs do not also accumulate in this condition

Question 19

What should the treatment strategy for a patient with LPL deficiency be and why?

Answer 19

Treatment:
a. Low fat diet (<15% of total calories from fat): will decrease the need for CM production.
b. Use coconut and palm oils for the majority of the fat: Medium‐chain triacylglycerols (MCTs; from coconut and/or palm oil) are useful because
they are absorbed as free fatty acids into the portal blood, avoiding the need to make
CMs. Note: It is not known why VLDLs do not also accumulate in this condition

Question 20

Compare and contrast a person who has been on the Atkins diet to an individual who has been starving for a week, prior to resuming a conventional diet.

Answer 20

I/G ratio: Lower in people starving for a week, since amino acids are minor stimulators of insulin release (Atkins Diet)
Glucokinase Activity: Lower in starved patient
Extent of hyperglycemia after carb ingestion: elevated in both, because of transcriptional regulation of glucose catabolism, but more elevated in starved patient.
Source of gluconeogenic amino acid precursors: ATKINS DIET: DIETARY PROTEIN AND MUSCLE PROTEIN (if post-absorptive)
Starved for a week: Muscle protein
(Thats the biggest difference!)