Triacylglycerol, Fatty Acids, Ketone Bodies, Glycogen

What enzyme breaks down triacylglycerols in adipose tissue?

Hormone-Sensitive Lipase (HSL)

What activates and inhibits HSL?

Activate: Glucagon, Epinephrine,

Inhibit: Insulin

After TAGs are broken down, what happens to glycerol?

Glycerol is released into the bloodstream and can be converted to glucose through gluconeogenesis in the liver.

Sent to liver → converted to DHAP for glycolysis or gluconeogenesis.

How are free fatty acids transported in blood?

Bound to albumin

What activates fatty acids before entering β-oxidation?

Fatty acyl-CoA synthetase catalyzes the conversion of free fatty acids to fatty acyl-CoA, which is necessary for their entry into β-oxidation.

Where does β-oxidation occur?

mitochondrial matrix

What is the purpose of the carnitine shuttle?

To transport long-chain fatty acyl-CoA molecules into the mitochondrial matrix for β-oxidation.

What inhibits CPT-I (carnitine shuttle)?

Malonyl-CoA (signals that fatty acid synthesis is ON)

What is needed for β-oxidation to occur?

Acyl-CoA, NAD⁺, FAD

What are the 4 steps of β-oxidation?

1. Oxidation (FAD → FADH₂)

2. Hydration

3. Oxidation (NAD⁺ → NADH)

4. Thiolysis (release acetyl-CoA)

What are the products of each β-oxidation cycle?

Answer: 1 FADH₂, 1 NADH, 1 acetyl-CoA, and a fatty acyl-CoA shortened by 2 carbons

Where are ketone bodies made?

Liver mitochondria (ONLY)

In what conditions are ketone bodies produced?

Fasting, starvation, uncontrolled diabetes, low-carb diets

What are the 3 ketone bodies?

• Acetoacetate
• β-hydroxybutyrate
• Acetone (exhaled)

Why does ketogenesis happen?

High acetyl-CoA from β-oxidation + low OAA (used for gluconeogenesis)

What tissues use ketone bodies?

Brain, muscle, heart.

What is the purpose of triacylglycerol breakdown (lipolysis)?

To release free fatty acids for energy and glycerol for gluconeogenesis, especially during fasting or exercise.

What hormones activate triacylglycerol breakdown?

Glucagon, epinephrine, and norepinephrine activate lipolysis by increasing cAMP, activating protein kinase A (PKA), which phosphorylates and activates hormone-sensitive lipase.

What hormone inhibits triacylglycerol breakdown?

Insulin, which activates a phosphatase that dephosphorylates and inactivates hormone-sensitive lipase.

What are the steps of triacylglycerol breakdown?

1. Triacylglycerol → Diacylglycerol
   Enzyme: Adipose triglyceride lipase

2. Diacylglycerol → Monoacylglycerol
   Enzyme: Hormone-sensitive lipase

3. Monoacylglycerol → Glycerol + Fatty acid
   Enzyme: Monoacylglycerol lipase

What happens to glycerol after lipolysis?

It travels to the liver and is converted to dihydroxyacetone phosphate (DHAP) for gluconeogenesis or glycolysis.

What enzyme activates fatty acids before breakdown?

Acyl-CoA synthetase, which converts a fatty acid into a fatty acyl-CoA using ATP (costs 2 ATP equivalent).

Why is the activation step important?

: It attaches coenzyme A to fatty acids, making them ready for transport into mitochondria and β-oxidation.

Why can’t long-chain fatty acids enter the mitochondria directly?

The inner mitochondrial membrane is impermeable to fatty acyl-CoA.

What are the steps of the carnitine shuttle?

• Fatty acyl-CoA + Carnitine → Fatty acyl-carnitine
  Enzyme: Carnitine palmitoyltransferase I (CPT-I)
  Location: outer mitochondrial membrane

• Transport of fatty acyl-carnitine into the matrix
  Enzyme: Carnitine-acylcarnitine translocase

• Fatty acyl-carnitine → Fatty acyl-CoA + Carnitine
  Enzyme: Carnitine palmitoyltransferase II (CPT-II)
  Location: inner mitochondrial membrane

What inhibits carnitine palmitoyltransferase I (CPT-I)?

Malonyl-CoA, the first committed intermediate of fatty acid synthesis.

Why does malonyl-CoA inhibit CPT-I?

to prevent fatty acid synthesis and oxidation from occurring at the same time.

What activates mitochondrial fatty acid transport?

Conditions of low insulin, high glucagon, fasting, exercise, and high AMP (low energy).

What is the purpose of β-oxidation?

To break down fatty acyl-CoA molecules into acetyl-CoA, NADH, and FADH₂ for ATP production.

What are the four repeating steps of β-oxidation?

1. Oxidation
   Enzyme: Acyl-CoA dehydrogenase
   Product: FADH₂

2. Hydration
   Enzyme: Enoyl-CoA hydratase

3. Oxidation
   Enzyme: Hydroxyacyl-CoA dehydrogenase
   Product: NADH

4. Thiolysis
   Enzyme: β-ketothiolase (thiolase)
   Product: Acetyl-CoA

What does each round of β-oxidation produce?

1 FADH₂
• 1 NADH
• 1 acetyl-CoA
• Fatty acyl-CoA shortened by 2 carbons

How many ATP does each product generate?

FADH₂ → 1.5 ATP
• NADH → 2.5 ATP
• Acetyl-CoA (via TCA cycle) → 10 ATP

What regulates β-oxidation?

Activators:
• Low insulin
• High glucagon
• High fatty acids
• High AMP
• Fasting/exercise

Inhibitors:
• Malonyl-CoA
• High ATP
• High NADH/FADH₂ (feedback)

What is the purpose of ketone bodies?

To provide an alternative energy source during low glucose states, especially for brain, heart, and muscle.

Why does the liver make ketones?

During fasting or low-insulin states:
• β-oxidation is high → produces excess acetyl-CoA
• Oxaloacetate is used for gluconeogenesis
• TCA cycle slows
• Acetyl-CoA is diverted to ketogenesis

What are the steps of ketone body synthesis?

• 2 Acetyl-CoA → Acetoacetyl-CoA
  Enzyme: Thiolase

• Acetoacetyl-CoA → HMG-CoA
  Enzyme: 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase
  (Rate-limiting step)

• HMG-CoA → Acetoacetate
  Enzyme: HMG-CoA lyase

• Acetoacetate → β-hydroxybutyrate (reduction)
  or
  Acetoacetate → Acetone (spontaneous decarboxylation)

How do tissues use ketone bodies?

1. β-hydroxybutyrate → acetoacetate

2. Acetoacetate → acetoacetyl-CoA
   Enzyme: Succinyl-CoA:acetoacetate CoA transferase (thiophorase)

3. Acetoacetyl-CoA → 2 acetyl-CoA
   → enters the TCA cycle

What regulates ketogenesis?

Activators:
• High acetyl-CoA
• High β-oxidation
• High glucagon
• Low insulin
• Low oxaloacetate

Inhibitors:
• High insulin
• High carbohydrate intake
• High oxaloacetate (TCA cycle running normally)

What is the purpose of triacylglycerol uptake?

To absorb dietary fats, package them into lipoproteins, transport them through the blood, and store them in adipose tissue or use them in muscle for energy.

Where are dietary triacylglycerols absorbed?

In the small intestine, specifically the enterocytes of the intestinal mucosa.

: How are dietary triacylglycerols broken down for absorption?

By pancreatic lipase, with the help of bile salts, into:
• free fatty acids
• monoacylglycerols

After absorption by enterocytes, how are triacylglycerols handled?

Enterocytes re-esterify them back into triacylglycerols and package them into chylomicrons (a type of lipoprotein).

What happens to chylomicrons after they are formed?

They enter the lymphatic system, then the bloodstream.

What enzyme is required for tissues to take up fatty acids from chylomicrons?

Lipoprotein lipase (LPL), located on the capillary endothelium.

What does lipoprotein lipase do?

Hydrolyzes triacylglycerols inside chylomicrons into free fatty acids and glycerol
• Allows tissues to take up fatty acids

Which tissues express lipoprotein lipase?

adipose tissue, skeletal muscle, and cardiac muscle.

What happens to the glycerol released by lipoprotein lipase?

: It returns to the liver for gluconeogenesis or glycolysis.

How do adipose cells take up fatty acids?

Free fatty acids diffuse into adipocytes and are re-esterified to make triacylglycerols for storage.

What regulates lipoprotein lipase levels in adipose vs muscle?

Adipose tissue (storage):
• ↑ insulin → ↑ LPL
Muscle (usage):
• ↑ epinephrine → ↑ LPL
• ↑ exercise → ↑ LPL

general summary (WRITE IT) 

Digestion: Pancreatic lipase + bile salts → FFA + MAG
Absorption: Enterocytes
Re-packaging: Re-esterified → chylomicrons
Transport: Lymph → bloodstream
Uptake enzyme: Lipoprotein lipase
Regulation:
• Insulin ↑ LPL in adipose
• Epinephrine ↑ LPL in muscle
Fates:
• Fatty acids → adipose (storage)
• Fatty acids → muscle (energy)
• Glycerol → liver
• Chylomicron remnants → liver

Where does glucose-6-phosphate (G6P) come from?

It comes from glucose being phosphorylated by hexokinase (muscle) or glucokinase (liver), which is step 1 of glycolysis.

What enzyme converts G6P to G1P?

Phosphoglucomutase (PGM).

Why does G6P convert to G1P?

Because G1P is the correct form needed to create activated glucose (UDP-glucose) for glycogen synthesis.

What two molecules react to form UDP-glucose?

Glucose-1-phosphate (G1P) and UTP.

What enzyme catalyzes G1P + UTP → UDP-glucose?

UDP-glucose pyrophosphorylase (also called UTP:glucose-1-phosphate uridylyltransferase).

What is the product of G1P + UTP?

UDP-glucose, plus pyrophosphate (PPi).

What happens to pyrophosphate (PPi)?

It is hydrolyzed into 2 inorganic phosphates (Pi), making the reaction irreversible.

What enzyme starts glycogen synthesis?

Glycogenin

What does glycogenin do?

It attaches the first few glucose molecules to itself using UDP-glucose to form a short primer chain.

Why is glycogenin needed?

Glycogen synthase cannot start a chain on its own; it requires a primer.

What enzyme elongates the glycogen chain?

Glycogen synthase.

What substrate does glycogen synthase use?

UDP-glucose.

What bond does glycogen synthase form?

α-1,4 glycosidic bonds.

What is released each time glycogen synthase adds a glucose?

UDP

What enzyme forms branches in glycogen?

The branching enzyme.

What does the branching enzyme do?

It moves a block of ~6–8 glucose units and attaches them to a new position via an α-1,6 bond

What enzyme removes glucose from glycogen?

Glycogen phosphorylase.

What does glycogen phosphorylase release?

Glucose-1-phosphate (G1P).

What molecule does glycogen phosphorylase use?

Inorganic phosphate (Pi) — NOT water.

When does glycogen phosphorylase stop working?

It stops 4 residues away from a branch point.

What enzyme removes branches during glycogen degradation?

The debranching enzyme.

What are the two activities of the debranching enzyme?

• Transferase — moves 3 glucose units to another chain

• Glucosidase — removes the last branch glucose using water

What does the glucosidase activity release?

Free glucose (not G1P).

What is the ratio of G1P to free glucose released from glycogen?

9 glucose-1-phosphate : 1 free glucose.

Is glycogen synthase active when phosphorylated or dephosphorylated?

Active when dephosphorylated.

Is glycogen phosphorylase active when phosphorylated or dephosphorylated?

Active when phosphorylated.

What hormone activates glycogen synthesis?

Insulin.

How does insulin activate glycogen synthase?

Insulin activates phosphatases, which remove phosphate groups → activates glycogen synthase.

What hormone activates glycogen breakdown in the liver?

Glucagon

What hormone activates glycogen breakdown in muscle?

Epinephrine

How do glucagon and epinephrine activate glycogen phosphorylase?

They activate kinases (like PKA) that phosphorylate the enzyme → turns it ON.

What allosteric molecule activates glycogen synthase in liver and muscle?

Glucose-6-phosphate (G6P).

What allosterically inhibits liver glycogen phosphorylase?

Glucose

What allosteric regulators activate muscle glycogen phosphorylase?

AMP and Ca²⁺.

Why does muscle glycogen phosphorylase respond to Ca²⁺?

Ca²⁺ rises during muscle contraction → signals energy need.

Which tissue responds to glucagon: liver or muscle?

Liver only (muscle does NOT have glucagon receptors).