Lipid Metabolism

Question 1

How do carbohydrate metabolism and lipid metabolism connect?

Answer 1

In glycolysis, pyruvate is created. That pyruvate is brought to the mitochondria where it is converted to acetyl-CoA with pyruvate dehydrogenase.

The acetyl-CoA is then involved in lipid metabolism with acetyl-CoA being converted to citrate and then fatty acids. Acetyl-CoA can also be converted to ketones.

Question 2

What is the purpose of fatty acid metabolism?

Answer 2

Serves as an alternate source for energy

Question 3

When is Fatty acid catabolism most active? What is involved?

Answer 3

Most active during fasting

Stimulated by glucagon

The liver converts fatty acids into ketone bodies for better distribution

Question 4

When is fatty acid synthesis most active?

Answer 4

Most active in the fed state

Stimulated by insulin

Cells synthesizing fatty acids participate in removal of glucose from serum

Liver exports newly synthesized fat to adipose tissue

Question 5

How does a patient present with too low of fatty acid catabolism?

Answer 5

Fatty acid catabolism is supposed to provide an alternative to glucose degradation for ATP production during fasting.

If fatty acid catabolism is too little, the liver does not have enough ATP to conduct gluconeogenesis. Insulin-responsive tissues keep burning glucose instead of fat.

Patient will present with fasting hypoglycemia with absence/low ketones and metabolic acidosis

Question 6

How does a patient present with too high of fatty acid catabolism?

Answer 6

Fatty acid metabolism is supposed to be shut off in fed state.

Insulin insufficiency (diabetes) leads to fatty acid mobilization in fed state.

Patient will present with hyperlipidemia with high serum concentrations of ketones.

Question 7

What is the chemistry of apolar lipids?

Answer 7

Form a water-free droplet

Completely hydrophobic

Examples include triacylglycerol, cholesteryl esters

Question 8

What do all lipids have in common?

Answer 8

Hydrophobic moiety

Question 9

What is the chemistry of amphipathic lipids?

Answer 9

Hydrophilic and hydrophobic properties

Form membrane bilayers or single layers around lipid droplet

Examples include membrane lipids cholesterol, and fatty acids

Question 10

How do most lipids travel?

Answer 10

Most diffuse through the plasma membrane.

BUT not when they are inside a large lipid droplet or bound to albumin

Fatty acid binding proteins in membrane facilitate diffusion

Question 11

What is the structure and chemistry of fatty acids?

Answer 11

Fatty acid is a long alkyl chain ending in carboxyl group

Alkyl chain is hydrophobic, carboxyl group is hydrophilic

Can be unsaturated - double bond between two carbons in alkyl chain

Naturally occurring double bonds are in cis configuration and double bonds in trans configuration are products of chemical processes

Question 12

Where can human enzymes desaturate lipids? Which are essential fatty acids?

Answer 12

Carbons 2-9

Fatty acids with double bonds beyond carbon 9 are essential

Question 13

What are examples of fatty acids that are essential and unsaturated?

Answer 13

Linoleate is ω6 (omega-6) and Linolenate is ω3 (omega-3)

Question 14

Can fatty acids form droplets by themselves?

Answer 14

No! Need glycerol

Question 15

What is the storage form of fatty acids?

Answer 15

Triacylglycerol (TAG, “fat”)

Question 16

How are fatty acids released from triacylglycerols? What are the different lipases for digestive tract, circulatory system, and intracellular?

Answer 16

Released by lipases that cleave bonds. Lipases break TAG from the diet or lipid droplet

Lipases of digestive tract - Lingual and pancreatic lipase

Lipase of circulatory system - Lipoprotein lipase

Intracellular lipases - Adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL)

Question 17

What is able to cross the plasma membrane?

Answer 17

Fatty acids and monoacylglycerol

Question 18

Where does fatty acid breakdown occur?

Answer 18

Mitochondria and peroxisomes

Mitochondria degrade fatty acids for energy and peroxisomes degrade for other processes.

Question 19

How are fatty acids activated when they enter the cytoplasm for breakdown?

Answer 19

Activated by binding to CoA. Long chain acyl-CoA (<20 carbons) are shuttled into mitochondria and very long chain acyl-CoA (>22 carbons) enter peroxisome for shortening

Question 20

Can fatty acids and acyl-CoA cross the inner mitochondrial membrane?

Answer 20

Inner mitochondrial membrane is impermeable to fatty acids and acyl-CoA

Medium and short chain fatty acids can cross without transporter

Question 21

Carnitine Shuttle

Answer 21

Two step shuttle system that helps import fatty acids into the mitochondrion. FAs shuttled by two carnitine-palmitoyl translocator (CPT) proteins

Steps:

1. CPT I moves the activated FA across the outer mitochondrial membrane and swaps CoA for a carnitine moiety
2. CPT II moves acyl-carnitine across the inner mitochondrial membrane and swaps the carnitine moiety back with CoA

Question 22

Carnitine

Answer 22

Small quaternary ammonium compound. Only known function is FA transport. Most carnitine taken up in diet

Question 23

What occurs with disorders to the carnitine shuttle? How do patients present?

Answer 23

Defects in any components of shuttle affect muscle function - muscles use FA even in fed state so defects range from mild muscle cramping to cardiomyopathy, death in infancy

Patient presents with fasting hypoglycemia –> Pt’s instructed to avoid periods of fasting

Genetic conditions:

1. CPT I and CPT II translocase deficiency
2. Primary carnitine deficiency - strictly vegetarian diet, poor uptake and transport of carnitine

Question 24

What happens once fatty acids enter the mitochondria?

Answer 24

Will be degraded

Question 25

How is the activated fatty acid degraded in the mitochondria?

Answer 25

Beta oxidation

Two oxidation reactions at Beta-carbon produce FADH and NADH

Question 26

How does beta oxidation occur?

Answer 26

1. Thiolase transfers a 2 carbon fragment of the fatty acid to coenzyme A to produce acetyl-CoA
2. During one cycle, acyl-CoA shortened by 2 carbons and electrons removed from FA are used to produce one molecule of FADH and NADH. Also produces acetyl-CoA
3. Acetyl-CoA oxidized in citric acid cycle and is further oxidized to Co2 and water in the mitochondria

Question 27

What happens to propionyl CoA after beta oxidation of odd chained fatty acids?

Answer 27

Becomes carboxylated to a four carbon molecule and becomes succinyl-CoA and participates in citric acid cycle or gluconeogenesis

Question 28

What is the energy content of fat?

Answer 28

Fat has 9 kcal/g of energy

Fat droplet do not contain water so they have higher energy than glycogen granules.

Question 29

What occurs with beta oxidation of odd chain fatty acids?

Answer 29

Beta oxidation of odd chain fatty acids produces one propionyl CoA (3 carbon)

Propionyl CoA converted into succinyl CoA (4 carbons) which can enter gluconeogenesis

Question 30

What needs to happen to unsaturated fatty acids in beta oxidation?

Answer 30

Require an additional enzyme for degradation - double bond in unsaturated FA is moved and isomerized, which produces the trans ∆2 - enoyl CoA intermediate

Enzyme is cis ∆3 enoyl-CoA
isomerase

Question 31

What enzymes catalyze the initial step of Beta oxidation?

Answer 31

Family of acyl-CoA dehydrogenases. Four isoforms for the different chain links - short, medium, long, and very long acyl-CoA dehydrogenases

Question 32

What is the most common Beta Oxidation disorder and what occurs with it?

Answer 32

Medium Acyl-CoA dehydrogenase (MCAD) is most common

Results in hypoketotic fasting hypoglycemia

See accumulation of C6-C12 fatty acids in urine, acyl-carnitines in blood

Question 33

How does the body deal with the problem that fatty acid uptake into cells and mitochondria is slow?

Answer 33

Liver produces ketone bodies from acetyl-CoA - they do not need to bind to albumin so they diffuse quickly

Liver produces a large amount of acetyl-CoA during fasting. 2 acetyl-CoA make one ketone body

Question 34

How does acetyl-CoA make ketones?

Answer 34

1. 3 Acetyl-CoA make 1 HMG-CoA
2. HMG-CoA lyase produces acetoacetate and acetyl CoA
3. Reduction of acetoacetate produces hydroxybutyrate
4. Decarboxylation of acetoacetate produces acetone

Question 35

What are the ketones produced by acetyl CoA?

Answer 35

Acetoacetate and hydroxybutyrate and Acetone

Question 36

What happens to acetoacetate and hydroxybutyrate and acetone after they are made?

Answer 36

Diffuse into the mitochondria of target cells

Ketones activated by transfer CoA

Acetoacetyl CoA split into 2 acetyl CoA - Ketone metabolism transfers acetyl-CoA from liver mitochondria to all other mitochondria

Acetone evaporates and is lost in breath - “fruity” breath