Ch 22 - Fatty Acid Metabolism

Fatty acids

Long hydrocarbon chains with a carboxylic acid group

Main functions of fatty acids

Energy storage, membrane components, signaling, protein anchors

Why are fatty acids energy-rich?

Highly reduced carbons yield more ATP than sugars

What stores fatty acids in the body?

Triacylglycerols (TAGs)

Why must bile salts be used in digestion?

TAGs are not water soluble

What do lipases do?

Break down TAGs into fatty acids and glycerol

What happens if bile salts are missing?

Fat digestion decreases significantly

What are chylomicrons?

Lipoproteins that transport dietary fats via lymph to blood

What happens if chylomicron formation fails?

Fat absorption decreases

Where are TAGs stored?

Adipose tissue lipid droplets

What activates fat breakdown?

Glucagon and epinephrine

What enzyme activates lipolysis?

Protein kinase A (PKA)

What does ATGL do?

Removes first fatty acid from TAG

What does hormone-sensitive lipase do?

Removes second fatty acid

What does MAG lipase do?

Removes final fatty acid

What happens if ATGL is deficient?

TAG accumulation (Chanarin-Dorfman syndrome)

How are free fatty acids transported?

Bound to albumin in blood

What happens if albumin is low?

Fatty acid transport decreases

What happens to glycerol in liver?

Converted to DHAP → glycolysis or gluconeogenesis

What happens if glycerol kinase is missing?

Glycerol cannot enter metabolism

Where does β-oxidation occur?

Mitochondria

What must happen before FA oxidation?

Activation with CoA

What enzyme activates fatty acids?

Acyl-CoA synthetase

What drives FA activation?

ATP hydrolysis

Why is FA activation irreversible?

Pyrophosphate hydrolysis

What happens if activation is blocked?

No β-oxidation occurs

How do long-chain fatty acids enter mitochondria?

Carnitine shuttle

What enzyme transfers FA to carnitine?

Carnitine acyltransferase I (CAT I)

What enzyme reforms acyl-CoA inside mitochondria?

CAT II

What happens if CAT I is inhibited?

Fat oxidation decreases

What inhibits CAT I?

Malonyl-CoA

What happens if carnitine is deficient?

Fatty acids cannot enter mitochondria

What is β-oxidation?

Sequential removal of 2-carbon units from fatty acids

Products of β-oxidation

FADH2, NADH, acetyl-CoA

What happens to FADH2 and NADH?

Used in oxidative phosphorylation

What happens to acetyl-CoA?

Enters citric acid cycle

What enzyme starts β-oxidation?

Acyl-CoA dehydrogenase

What does acyl-CoA dehydrogenase produce?

FADH2 and trans double bond

What happens if acyl-CoA dehydrogenase is missing?

Fat oxidation impaired → hypoglycemia

What enzyme hydrates the double bond?

Enoyl-CoA hydratase

What does enoyl-CoA hydratase add?

Water

What enzyme oxidizes hydroxyl group?

3-hydroxyacyl-CoA dehydrogenase

What cofactor is used?

NAD+

What enzyme cleaves fatty acid?

Ketothiolase

What is released each cycle?

Acetyl-CoA

What happens if ketothiolase is inhibited?

β-oxidation stops

What is special about odd-chain fatty acids?

End in propionyl-CoA

What does propionyl-CoA become?

Succinyl-CoA

What vitamin is required?

Vitamin B12

What happens if B12 is deficient?

Methylmalonic acidemia

What happens if propionyl-CoA cannot convert?

CAC intermediates decrease

What is the fate of succinyl-CoA?

Enters citric acid cycle

What happens with unsaturated fatty acids?

Require isomerase and reductase

What enzyme fixes double bonds?

Enoyl-CoA isomerase

What happens if isomerase is missing?

Unsaturated FA oxidation impaired

What enzyme handles conjugated double bonds?

2,4-dienoyl-CoA reductase

What cofactor does reductase use?

NADPH

What happens if reductase is missing?

Polyunsaturated FA oxidation impaired

What are peroxisomes used for?

Break down very long fatty acids

What happens in peroxisomes?

FADH2 transfers electrons to O2

What is produced in peroxisomes?

H2O2

What enzyme breaks down peroxide?

Catalase

What happens if peroxisomes fail?

Neurodegeneration

What disease involves peroxisome failure?

Zellweger syndrome

What is Lorenzo’s oil used for?

Reduce very long fatty acids

What happens if VLFA accumulate?

Neurodegeneration

Why are carbohydrates needed for fat metabolism?

Provide oxaloacetate

What happens if OAA is low?

Acetyl-CoA accumulates

What happens to excess acetyl-CoA?

Converted to ketone bodies

What is the first ketone body intermediate?

Acetoacetyl-CoA

What enzyme forms acetoacetyl-CoA?

Ketothiolase (reverse)

What is HMG-CoA?

Intermediate in ketone synthesis

What produces acetoacetate?

HMG-CoA cleavage

What happens to acetoacetate?

Forms acetone or β-hydroxybutyrate

What tissues use ketone bodies?

Brain, heart, kidney

What happens if ketone bodies accumulate?

Ketoacidosis

What causes diabetic ketoacidosis?

Low insulin → high FA breakdown

Why does pH drop in ketoacidosis?

Ketone bodies are acidic

Why can’t fatty acids make glucose?

Acetyl-CoA cannot become pyruvate

What is fatty acid synthesis location?

Cytoplasm

What is degradation location?

Mitochondria

What carrier is used in synthesis?

ACP (acyl carrier protein)

What cofactor is used in synthesis?

NADPH

What is first step of FA synthesis?

Acetyl-CoA → malonyl-CoA

What enzyme catalyzes this?

Acetyl-CoA carboxylase

What type of reaction is this?

ATP-dependent carboxylation

Why is this step important?

Committed step

What happens if ACC is inhibited?

No FA synthesis

What activates ACC?

Insulin, citrate

What inhibits ACC?

AMPK, palmitoyl-CoA

What happens if AMP is high?

FA synthesis decreases

What happens if ATP is high?

FA synthesis increases

What does malonyl-CoA do besides synthesis?

Inhibits CAT I

What happens if malonyl-CoA is high?

FA oxidation decreases

What is fatty acid synthase?

Multi-enzyme complex

What does MAT do?

Transfers acetyl/malonyl to ACP

What does KS do?

Condensation reaction

What does KR do?

Reduction step

What does DH do?

Dehydration step

What does ER do?

Final reduction