Chapter 9— Lipid Metabolism

Fatty acids have 4 major physiological roles:

1. Fuel molecules

- Fatty acids are a primary source of energy during rest and moderate exercise.

2. Building blocks

- Fatty acids are building blocks of phospholipids and glycolipids.

3. Protein modification

• Fatty acids can attach to proteins through covalent attachment.

• This helps target proteins to membrane locations.

4. Hormones and messengers

- Fatty acid derivatives serve as hormones and intracellular messengers.

Triacylglycerols (triglycerides):

Uncharged esters of fatty acids with glycerol.

 Why are triacylglycerols a major source of energy?

They are highly reduced and contain no water, allowing them to store concentrated amounts of metabolic energy.

Where are triacylglycerols stored in the body?

- Mainly in adipose tissue and also in muscle for energy needs.

Lipases:

• Intestinal enzymes that break down triacylglycerols into:

  • Free fatty acids

  • Monoacylglycerol

• Secreted by the pancreas into the intestine.

Lipids exit the stomach as

emulsion (particles with a triacylglycerol core surrounded by cholesterol and cholesterol esters).

- Bile acids:

• Amphipathic molecules that help lipases digest lipids.

• Synthesized from cholesterol in the liver and secreted from the gallbladder.

• Orient ester bonds so lipases can access and digest them in an aqueous environment.

- Colipase:

• A protein that binds lipase to the lipid particle, allowing lipid breakdown.

• Secreted by the pancreas.

Dietary Lipids Are Transported in Chylomicrons: 1. Breaking Down the Fats

• In the intestine, lipases break triacylglycerols down into:

  • Free fatty acids

  • Monoacylglycerol

• These smaller molecules can enter intestinal cells.

Dietary Lipids Are Transported in Chylomicrons: 2. Getting Fats Into Intestinal Cells

• Micelles:

  • Carry free fatty acids and monoacylglycerol to the plasma membrane of intestinal epithelial cells.

  • Help transport these fat digestion products through the watery environment of the intestine.

• FATPs (fatty-acid transport proteins):

  • Membrane proteins that help transport free fatty acids across the intestinal cell membrane.

• FABPs (fatty-acid binding proteins):

  • Pick up free fatty acids and monoacylglycerol inside the cell.

  • Carry them through the cytoplasm to the smooth ER.

Dietary Lipids Are Transported in Chylomicrons: 3. Rebuilding Triacylglycerols

• Inside the smooth ER, free fatty acids and monoacylglycerol are reassembled into triacylglycerols.

• The fats were broken down for digestion, but they need to be put back together for transport through the body.

Dietary Lipids Are Transported in Chylomicrons: 4. Forming Chylomicrons

The newly formed triacylglycerols are packaged into particles called chylomicrons.

• Chylomicrons are lipoprotein transport particles.

• They contain:

  • Triacylglycerols

  • Proteins

  • Phospholipids

  • Cholesterol

Fats do not mix well with the watery environment of the blood. Chylomicrons package the fats into particles that can transport them through the body. Chylomicrons are released from intestinal cells and eventually enter the bloodstream.

Chylomicron Degradation

• Membrane-bound lipases at adipose tissue and muscle break down the triacylglycerols carried by chylomicrons.

• This releases fatty acids that can be taken up by the tissues.

Fatty Acid Breakdown for Energy: Stage 1: Mobilization (Releasing Fatty Acids)

• Glucagon: Signals that glucose availability is low.

• Epinephrine: Signals that the body needs energy, such as during exercise.

• Both hormones activate Protein Kinase A (PKA) through their receptors.

• PKA phosphorylates two proteins:

  • Perilipin: A protein associated with fat droplets.

  • Hormone-sensitive lipase (HSL): An enzyme involved in breaking down stored fats.

What Does Phosphorylated Perilipin Do?

When perilipin is phosphorylated, it helps mobilize stored fat in two ways:

1. Restructures the fat droplet so triacylglycerols are more accessible to breakdown.

2. Releases a coactivator for adipose triglyceride lipase (ATGL), helping activate ATGL.

Completion of Fatty Acid Mobilization

1. ATGL: Breaks triacylglycerol into diacylglycerol + a free fatty acid.

2. Hormone-sensitive lipase (HSL): Breaks diacylglycerol into monoacylglycerol + a free fatty acid.

3. Monoacylglycerol lipase: Breaks monoacylglycerol into glycerol + a free fatty acid.

Final products: 3 free fatty acids + 1 glycerol per triacylglycerol.

• Ethanol can inhibit the signaling pathway involved in mobilization

Free Fatty Acids and Glycerol Are Released into the Blood

• Albumin is a protein that transports fatty acids in the blood

• Glycerol is absorbed by the liver broken down to glyceraldehyde 3-phosphate

Where Do the Products Go?: Free fatty acid

Will go to other tissues and oxidize the fatty acid, producing Acetyl-CoA which can undergo Kreb Cycle.

Where Do the Products Go?: Glycerol

• Travels to the liver.

• Converted to glyceraldehyde 3-phosphate (G3P).

The liver processes glycerol according to the body's needs:

• Glycolysis: Glycerol can be used to produce energy and eventually form pyruvate.

• Gluconeogenesis: Glycerol can be used to make glucose, which can be released into the blood for other tissues.

Fatty Acid Breakdown for Energy: Stage 2: Activation and Transport: Step 1

• Fatty acids enter target cells and are transported within the cell to the mitochondria

• Before fatty acids can be broken down, they must be activated by attachment to coenzyme A (CoA).

• Acyl-CoA synthetase: The enzyme that attaches CoA to a fatty acid, forming fatty acyl-CoA.

• This forms a thioester linkage between the fatty acid and CoA.

• The reaction requires ATP.

• Activation takes place at the outer mitochondrial membrane.

Fatty Acid Breakdown for Energy: Stage 2: Activation and Transport: Step 2 Transport Into the Mitochondria

• Activated long-chain fatty acids cannot cross the inner mitochondrial membrane on their own.

• Carnitine: -OH with both a positive and a negative charge that helps transport activated fatty acids into the mitochondrial matrix.

• The fatty acid is temporarily attached to carnitine so it can cross the inner mitochondrial membrane

Fatty Acid Breakdown for Energy: Stage 3: Breakdown Into Acetyl-CoA (β-Oxidation)

 Break fatty acids into acetyl-CoA so they can enter the citric acid cycle.

• β-oxidation occurs in the mitochondrial matrix.

• The fatty acid chain is broken down two carbons at a time.

• Each round involves 4 steps:

Step	Reaction	What happens?
1	Oxidation by FAD	FAD is reduced to FADH₂.
2	Hydration	Water is added.
3	Oxidation by NAD⁺	NAD⁺ is reduced to NADH.
4	Thiolysis by CoA	The chain is split, releasing acetyl-CoA.

Why do unsaturated fatty acids require additional steps for degradation?

• Unsaturated fatty acids contain one or more double bonds.

• Their double bonds must be processed by additional enzymes before β-oxidation can continue.

• An odd number of double bonds requires isomerase, while an even number requires both isomerase and reductase.

 What happens during the breakdown of odd-chain fatty acids?

• The final round of β-oxidation produces propionyl-CoA, which is converted into succinyl-CoA.

• Succinyl-CoA can enter the citric acid cycle or contribute to glucose biosynthesis.

What is the role of peroxisomes in fatty acid oxidation?

• Peroxisomes shorten very long-chain and branched fatty acids, making them better substrates for β-oxidation in mitochondria.

What are ketone bodies? (Slides 23–25)

Ketone bodies are water-soluble forms of acetyl units produced from acetyl-CoA. The three ketone bodies are acetoacetate, D-3-hydroxybutyrate, and acetone. During fasting or diabetes, the liver produces ketone bodies when oxaloacetate is used for gluconeogenesis. They travel through the blood to tissues such as the heart, kidneys, and brain, where they are converted back into acetyl-CoA to produce energy.

Ketone Body Formation

• Two molecules of acetyl-CoA join together.

• CoA groups are removed as the molecules combine and are processed.

• This forms HMG-CoA (hydroxymethylglutaryl-CoA).

• HMG-CoA can be used to make:

  • Cholesterol, if the body needs it.

  • Ketone bodies, which can be used as an alternative fuel source.

Fatty Acid Synthesis vs. Fatty Acid Breakdown

Fatty Acid Synthesis	Fatty Acid Breakdown
Builds fatty acids	Breaks down fatty acids
Occurs in the cytoplasm	Occurs in the mitochondrial matrix
Uses acyl carrier protein (ACP)	Uses coenzyme A (CoA)
Uses malonyl-ACP to donate 2-carbon units	Produces acetyl-CoA
Uses NADPH	Uses NAD⁺ and FAD

Formation of Malonyl-CoA

• Acetyl-CoA carboxylase adds carbon dioxide (CO₂) to acetyl-CoA.

• This produces malonyl-CoA.

How does citrate facilitate transport of acetyl-CoA into the cytoplasm? (Slides 30–31)

Acetyl-CoA combines with oxaloacetate in the mitochondrial matrix to form citrate. Citrate can cross the mitochondrial membranes and enter the cytoplasm, where ATP-citrate lyase splits it into acetyl-CoA and oxaloacetate. The acetyl-CoA is then used for fatty acid synthesis.

ACC1: Regulation

Regulator	Effect on ACC1	Result
AMPK phosphorylates ACC1	Inhibits ACC1	Decreases fatty acid synthesis
Protein phosphatase 2A removes the phosphate	Activates ACC1	Increases fatty acid synthesis
Citrate	Activates ACC1	Increases fatty acid synthesis
Palmitoyl-CoA	Inhibits ACC1	Decreases fatty acid synthesis

How Phosphorylation Controls ACC

Phosphorylated ACC = INACTIVE = decreased fatty acid synthesis.

Dephosphorylated ACC = ACTIVE = increased fatty acid synthesis.

Why does AMPK inhibit ACC1?

• AMPK is activated when AMP levels are high, signaling that the cell has low energy.

• The cell needs to make ATP, not spend energy building fatty acids.

• Therefore, AMPK inhibits ACC1 and fatty acid synthesis.

- Why does citrate activate ACC1?

• Citrate in the cytoplasm signals that building blocks are available for fatty acid synthesis.

• Citrate activates ACC1 so synthesis can begin.

- Why does palmitoyl-CoA inhibit ACC1?

• Palmitoyl-CoA signals that fatty acid products are already available.

• It inhibits ACC1 to prevent unnecessary fatty acid synthesis.

How does ACC2 regulate fatty acid breakdown when energy is LOW?

• Energy is low → AMP increases.

• AMPK becomes activated.

• AMPK phosphorylates and inhibits ACC2.

• ACC2 produces less malonyl-CoA.

• Less malonyl-CoA means less inhibition of CPT I.

• CPT I allows more fatty acids to enter the mitochondria.

• Fatty acid breakdown (oxidation) increases to produce ATP

How does ACC2 regulate fatty acid breakdown when energy is HIGH(Low AMP)?

• Energy is high → ATP increases.

• AMPK activity decreases.

• ACC2 becomes dephosphorylated and active.

• ACC2 produces more malonyl-CoA.

• Malonyl-CoA inhibits CPT I.

• Fewer fatty acids enter the mitochondria.

• Fatty acid breakdown (oxidation) decreases.

Hormonal Regulation of ACC

Hormone	Effect	Result
Glucagon	Increases AMPK activity	Inhibits ACC and fatty acid synthesis
Epinephrine	Increases AMPK activity	Inhibits ACC and fatty acid synthesis
Insulin	Inhibits AMPK and promotes ACC dephosphorylation	Activates ACC and fatty acid synthesis

Making Phosphatidate: Step 1

Reactant: Dihydroxyacetone phosphate(DHAP)

Product: Glycerol-3-Phosphate

Cofactors: NADH is oxidized to NAD

Making Phosphatidate: Step 2

Reactants: Glycerol-3-Phosphate + Fatty Acyl Coenzyme A

Product: Monoacylglycerol-3-Phosphate

Byproduct: CoA is released.

Making Phosphatidate: Step 3

Reactants: Monoacylglycerol-3-Phosphate + Fatty Acyl Coenzyme A

Product: Phosphatidate

Byproduct: CoA is released

How to make Phosphatidate into Phospholipids

Addition of polar head groups to phosphate groups using CTP as energy source

Cholesterol Synthesis

The process begins with the production of mevalonate.

The key enzyme is HMG-CoA reductase, which converts HMG-CoA into mevalonate.

Steps of the LDL pathway:

1. LDL carrying cholesterol travels through the blood.

2. LDL binds to receptors on the surface of liver cells.

3. The cell membrane folds inward and brings LDL into the cell through receptor-mediated endocytosis.

4. The vesicle is broken down, releasing cholesterol.

5. LDL proteins are broken down into amino acids that can be recycled.

6. The free cholesterol can enter the smooth endoplasmic reticulum (ER), where it can be used to make bile acids and bile salts.

How the Liver Processes Cholesterol

Once inside the endoplasmic reticulum, the liver hepatocyte can convert cholesterol to bile acids and bile salts. These are conjugated to polar molecules to increase their polarity.

• Transported out of the liver through the bile duct for elimination.

What Are Lipoproteins?

Joining lipids with proteins makes them easier to transport through watery fluids like blood.

• Protein is denser than lipid, so:

  • More protein = higher density.

  • More lipid and less protein = lower density.

Different Classes of Lipoproteins

• Chylomicrons

• VLDL (very-low-density lipoproteins)

• IDL (intermediate-density lipoproteins)

• LDL (low-density lipoproteins)

• HDL (high-density lipoproteins)

Chylomicrons

• Synthesized in the intestinal wall.

• Carry lipids absorbed from the gastrointestinal tract to the liver and other parts of the body.

• Contain a large proportion of lipid compared with protein.

• Therefore, they have very low density.

VLDL

• Synthesized in the liver.

• Carry lipids made by the body to peripheral tissues.

• Contain a large proportion of lipid compared with protein.

• Therefore, they also have very low density.

Why is HDL good cholesterol, yet LDL is bad?

• HDL is good because it collects excess cholesterol from tissues and blood vessel walls and carries it back toward the liver. This helps reduce cholesterol buildup and plaque formation.

• LDL is bad because excess LDL can deposit cholesterol in blood vessel walls, contributing to plaque formation. Plaques narrow the vessels and restrict blood flow.

Familial Hypercholesterolemia (FH)

• Defect: Defective LDL receptors.

• Inheritance: Autosomal dominant.

• Result: The body cannot remove LDL cholesterol from the blood effectively, causing high LDL levels.

 Tay-Sachs Disease

• Defect: Absence of the enzyme hexosaminidase A.

• Normally: Hexosaminidase A breaks down gangliosides.

• Result: Gangliosides build up in the brain.

Gaucher’s Disease

• Defect: Lack of the enzyme glucocerebrosidase.

• Normally: This enzyme breaks down glucocerebroside.

• Result: Glucocerebroside accumulates in cells.

• Inheritance: Autosomal recessive.

Krabbe Disease

• Defect: Lack of the enzyme galactocerebrosidase, caused by mutations in the GALC gene.

• Normally: This enzyme breaks down galactocerebroside.

• Result: Lipid breakdown is impaired.

• Inheritance: Autosomal recessive.