Lipid Metabolism Notes

Lipid Metabolism Chapter Outline

25.1 Digestion and Absorption of Lipids
25.2 Triacylglycerol Storage and Mobilization
25.3 Glycerol Metabolism
25.4 Oxidation of Fatty Acids
25.5 ATP Production from Fatty Acid Oxidation
25.6 Ketone Bodies
25.7 Biosynthesis of Fatty Acids: Lipogenesis
25.8 Relationship Between Lipogenesis and Citric Acid Cycle Intermediates
25.9 Biosynthesis of Cholesterol
CHEMISTRY AT A GLANCE: Interrelationships Between Carbohydrate and Lipid Metabolism
25.10 Relationships Between Lipid and Carbohydrate Metabolism
CHEMICAL CONNECTIONS
- High-Intensity Versus Low-Intensity Workouts
- Statins: Drugs That Lower Plasma Levels of Cholesterol

Introduction to Lipid Metabolism

Lipids, particularly triacylglycerols, are a major energy-rich fuel stored in adipose tissue.
Lipids contribute a significant portion (one-third to one-half) of the average U.S. diet's caloric intake.
Excess energy from carbohydrates and proteins is converted into lipids for storage in adipose tissue.

25.1 Digestion and Absorption of Lipids

Triacylglycerols (TAGs):
- Constitute 98% of dietary lipids.
- Are the primary focus of this chapter.
- Insoluble in water, limiting the effect of salivary enzymes.
Digestion Process:
- Stomach:
  - TAGs undergo physical changes due to churning, breaking them into small globules.
  - These globules form a layer above other food components, creating chyme.
  - Gastric lipase enzymes hydrolyze about 10% of TAGs in the stomach. High-fat diets can induce higher lipase production.
- Small Intestine:
  - Cholecystokinin hormone triggers the release of bile from the gallbladder.
  - Bile emulsifies TAG globules, allowing pancreatic lipases to hydrolyze ester linkages.
  - Pancreatic lipases typically liberate two fatty acid units, producing a monoacylglycerol and two free fatty acids.
  - Complete hydrolysis can occur, resulting in free glycerol.
  - $\text{Triacylglycerol} + 2H_2O \xrightarrow{\text{Lipases}} \text{Monoacylglycerol} + 2 \text{Fatty acids}$
  - $\text{Triacylglycerol} + 3H_2O \xrightarrow{\text{Lipases}} \text{Glycerol} + 3 \text{Fatty acids}$
- Micelle Formation:
  - Free fatty acids and monoacylglycerols combine with bile to form micelles.
  - Micelles are small and easily absorbed through intestinal cell membranes.
- Repackaging in Intestinal Cells:
  - Fatty acids and monoacylglycerols are reassembled into triacylglycerols.
  - These TAGs combine with membrane lipids (phospholipids and cholesterol) and water-soluble proteins to form chylomicrons.
- Chylomicrons:
  - Lipoproteins that transport TAGs from intestinal cells to the bloodstream via the lymphatic system.
  - TAGs constitute 95% of the core lipids in a chylomicron.
  - Chylomicrons are too large to directly enter capillaries and are delivered to the bloodstream via the lymphatic system through the thoracic duct.
- Hydrolysis in the Bloodstream:
  - TAGs in chylomicrons are hydrolyzed by lipoprotein lipases into glycerol and free fatty acids.
  - Lipoprotein lipases are located on blood vessel linings in muscle and other tissues.
  - The hydrolysis products are absorbed by cells, either broken down for energy or stored as lipids.
- Chylomicron concentrations increase 2-6 hours after a meal, then decrease as they move into adipose cells or the liver.

25.2 Triacylglycerol Storage and Mobilization

Adipocytes:
- Specialized cells in adipose tissue that store TAGs.
- Adipose tissue is located under the skin and around vital organs.
- Functions include energy storage, insulation, and organ protection.
- Characterized by a large triacylglycerol droplet that fills most of the cell's volume.
Triacylglycerol Mobilization:
- Hormones like epinephrine and glucagon trigger the use of stored TAGs.
- Hormones stimulate cAMP production inside the adipose cell.
- cAMP activates hormone-sensitive lipase (HSL) through phosphorylation.
- HSL hydrolyzes TAGs, releasing fatty acids and glycerol into the bloodstream.
- Triacylglycerol mobilization is an ongoing process, with about 10% of TAGs being replaced daily.
Energy Reserves:
- TAGs in adipose tissue are the body’s primary source of stored energy.
Table 25.1 Stored Energy Reserves of Various Types for a 150-lb (70-kg) Person
- Triacylglycerol: 135,000 kcal; 84.3%
- Protein: 24,000 kcal; 15%
- Glycogen: 720 kcal; 0.45%
- Blood Glucose: 80 kcal; 0.05%
- Stored TAGs in adipose tissue supply approximately 60% of the body’s energy needs when the body is in a resting state.

25.3 Glycerol Metabolism

Process:
- Glycerol, produced during triacylglycerol mobilization, enters the bloodstream and travels to the liver or kidneys.
- It is converted to dihydroxyacetone phosphate in a two-step process.
- Step 1: Phosphorylation of a primary hydroxyl group of the glycerol by glycerol kinase.
  - $\text{Glycerol} + ATP \rightarrow \text{Glycerol 3-phosphate} + ADP$
- Step 2: Oxidation of glycerol’s secondary alcohol group (C-2) to a ketone by glycerol 3-phosphate dehydrogenase.
  - $\text{Glycerol 3-phosphate} + NAD^+ \rightarrow \text{Dihydroxyacetone phosphate} + NADH + H^+$
Overall Reaction:
- $\text{Glycerol} + ATP + NAD^+ \rightarrow \text{Dihydroxyacetone phosphate} + ADP + NADH + H^+$
Fate of Dihydroxyacetone Phosphate:
- An intermediate in glycolysis and gluconeogenesis.
- Can be converted to pyruvate, then acetyl CoA, and finally carbon dioxide.
- Can be used to form glucose.

25.4 Oxidation of Fatty Acids

Process Overview:
- Fatty acids are broken down to obtain energy.
Steps:
- Activation: Fatty acid is activated by bonding to coenzyme A.
  - Occurs on the outer mitochondrial membrane.
  - Reactants: fatty acid, coenzyme A, and ATP.
  - ATP is converted to AMP, and pyrophosphate (PPi) is hydrolyzed to 2Pi.
  - The product is Acyl CoA.
  - $\text{Fatty acid} + CoA + ATP \rightarrow \text{Acyl CoA} + AMP + 2Pi$
- Transport: Fatty acid is transported into the mitochondrial matrix via a shuttle mechanism involving carnitine.
  - Acyl CoA is too large to pass through the inner mitochondrial membrane.
- β-Oxidation: Fatty acid is repeatedly oxidized, cycling through a series of four reactions to produce acetyl CoA, FADH2, and NADH.
  - Occurs in the mitochondrial matrix.
  - Each repetition generates an acetyl CoA molecule and an acyl CoA molecule that has two fewer carbon atoms.
  - For saturated fatty acids, the process involves:
    - Alkane → alkene → secondary alcohol → ketone
    - Oxidation (dehydrogenation), Hydration, Oxidation (dehydrogenation), Chain cleavage
Reactions of the β-Oxidation Pathway:
- Step 1: Oxidation (dehydrogenation).
  - Hydrogen atoms are removed from the α and β carbons, creating a double bond.
  - FAD is the oxidizing agent; FADH2 is produced.
  - $\text{Acyl CoA} + FAD \rightarrow \text{trans-Enoyl CoA} + FADH_2$
- Step 2: Hydration.
  - A molecule of water is added across the trans double bond, producing a secondary alcohol at the β-carbon.
  - $\text{trans-Enoyl CoA} + H_2O \rightarrow L-\beta\text{-Hydroxyacyl CoA}$
- Step 3: Oxidation (dehydrogenation).
  - The β-hydroxy group is oxidized to a ketone functional group with NAD+ serving as the oxidizing agent.
  - $L-\beta\text{-Hydroxyacyl CoA} + NAD^+ \rightarrow \beta\text{-Ketoacyl CoA} + NADH + H^+$
- Step 4: Chain Cleavage.
  - The fatty acid chain is broken between the α and β carbons by reaction with a coenzyme A molecule.
  - $\beta\text{-Ketoacyl CoA} + CoA \rightarrow \text{Acetyl CoA} + \text{Acyl CoA}$
  - A new acyl CoA molecule is produced which is shorter by two carbon atoms than its predecessor.
  - The acyl CoA is recycled through the same set of four reactions.
Unsaturated Fatty Acids:
- Require two additional enzymes for oxidation: an epimerase and a cis–trans isomerase.
  - The epimerase changes a D configuration to an L configuration.
  - The cis–trans isomerase produces a trans-(2,3) double bond from a cis-(3,4) double bond.

25.5 ATP Production from Fatty Acid Oxidation

Stearic Acid (18:0) Oxidation:
- Requires 8 repetitions of the β-oxidation pathway.
- Produces 9 acetyl CoA molecules, 8 FADH2 molecules, and 8 NADH molecules.
- Processing through the citric acid cycle, electron transport chain, and oxidative phosphorylation yields:
  - 8 NADH → 20 ATP (2.5 ATP/NADH)
  - 8 FADH2 → 12 ATP (1.5 ATP/FADH2)
  - 9 acetyl CoA → 90 ATP (10 ATP/acetyl CoA)
- Gross ATP production: 122 ATP
- Net ATP production: 120 ATP (subtracting 2 ATP for fatty acid activation)
Comparison with Glucose Oxidation:
- Stearic acid produces four times as much ATP as glucose.
- Lipids are 33% more efficient than carbohydrates as energy-storage systems on the basis of equal number of carbon atoms.
Energy per Gram Comparison:
- Fatty acids produce 2.5 times as much energy per gram as carbohydrates (glucose).
Fuel Use in the Human Body:
- Skeletal muscle:
  - Uses glucose (from glycogen) when active.
  - Uses fatty acids when at rest.
- Cardiac muscle:
  - Depends primarily on fatty acids, secondarily on ketone bodies, glucose, and lactate.
- Liver:
  - Uses fatty acids as the preferred fuel.
- Brain:
  - Maintained by glucose and ketone bodies.
  - Fatty acids cannot cross the blood–brain barrier.
CHEMICAL CONNECTIONS: High-Intensity Versus Low-Intensity Workouts
- In a resting state, the human body burns more fat than carbohydrate (2/3 fat and 1/3 carbohydrate)
- Initial stages of exercise are fueled primarily by glucose; in later stages, TAGs become the primary fuel.

25.6 Ketone Bodies

Definition:
- Acetoacetate, β-hydroxybutyrate, and acetone are ketone bodies produced from acetyl CoA when there is an excess of acetyl CoA from fatty acid degradation due to triacylglycerol–carbohydrate metabolic imbalances.
Conditions Leading to Ketone Body Formation:
- Dietary intake high in fat and low in carbohydrates.
- Diabetic conditions where the body cannot adequately process glucose.
- Prolonged fasting or starvation, where glycogen supplies are exhausted.
Formation Process:
- Excess acetyl CoA is diverted to the formation of ketone bodies when oxaloacetate supplies are too low for the citric acid cycle.
- The production of ketone bodies occurs in liver mitochondria.
- Acetoacetate is the first ketone body to be produced.
- Acetoacetate can synthesized is converted to β-hydroxybutyrate.
- Synthesized ketoacetate and hydroxybutyrate are released to the bloodstream where acetone it’s produced.
- Acetone is a volatile substance that’s excreted by exhalation.
  - Its sweet odor is detectable in the breath of a diabetic.
Reactions Among Ketone Bodies:
- Reduction of acetoacetate produces β-hydroxybutyrate.
- $\text{Acetoacetate} + NADH + H^+ \rightarrow \beta\text{-Hydroxybutyrate} + NAD^+$
- Decarboxylation of acetoacetate produces acetone.
- $\text{Acetoacetate} \rightarrow \text{Acetone} + CO_2$
Ketone Bodies as Energy Sources:
- Serve as sources of energy for various tissues.
- Important energy sources in heart muscle and the renal cortex.
- The brain can adapt to obtain a portion of its energy from ketone bodies in dieting situations.
Ketogenesis:
- Begins as two acetyl CoA molecules combine to produce acetoacetyl CoA.
- $\text{Acetyl CoA} + \text{Acetyl CoA} \rightarrow \text{Acetoacetyl CoA} + CoA$
- Acetoacetyl CoA reacts with a third acetyl CoA and water to produce 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) and CoA.
- $\text{Acetoacetyl CoA} + \text{Acetyl CoA} + H_2O \rightarrow \text{HMG-CoA} + CoA$
- HMG-CoA is cleaved to acetyl CoA and acetoacetate.
- $\text{HMG-CoA} \rightarrow \text{Acetoacetate} + \text{Acetyl CoA}$
- Acetoacetate is reduced to β-hydroxybutyrate.
  - $\text{Acetoacetate} + NADH + H^+ \rightarrow \beta\text{-Hydroxybutyrate} + NAD^+$
Energy Production from Acetoacetate:
- Acetoacetate is activated by transfer of a CoA group from succinyl CoA.
- The resulting acetoacetyl CoA is then cleaved to give two acetyl CoA molecules that can enter the citric acid cycle.
Ketosis:
- Excess accumulation of ketone bodies in blood (ketonemia) and urine (ketonuria).
- Often detectable by the smell of acetone on a person’s breath.
- Symptoms: headache, dry mouth, and sometimes foul-smelling breath.
- Acidosis from elevated ketone body levels is often called ketoacidosis or metabolic acidosis.

25.7 Biosynthesis of Fatty Acids: Lipogenesis

Lipogenesis is the metabolic pathway by which fatty acids are synthesized from acetyl CoA.
Lipogenesis is not simply a reversal of the steps for degradation of fatty acids (the β-oxidation pathway).
Differences between Lipogenesis and Fatty Acid Degradation:
- Location:
  - Lipogenesis occurs in the cell cytosol.
  - Fatty acid degradation occurs in the mitochondrial matrix.
- Enzymes:
  - Lipogenesis enzymes are collected into a multienzyme complex called fatty acid synthase.
  - Enzymes involved in fatty acid degradation are not physically associated.
- Intermediates:
  - Intermediates of lipogenesis are bonded to ACP (acyl carrier protein).
  - The carrier for fatty acid degradation intermediates is CoA.
- Reducing/Oxidizing Agents:
  - Fatty acid synthesis is dependent on the reducing agent NADPH.
  - Fatty acid degradation is dependent on the oxidizing agents FAD and NAD+.
- Building Blocks:
  - Fatty acids are built up two carbons at a time during synthesis and are broken down two carbons at a time during degradation.
Lipogenesis occurs any time dietary intake provides more nutrients than are needed for energy requirements.
Primary lipogenesis sites are the liver, adipose tissue, and mammary glands.
Citrate–Malate Shuttle System:
- Transports acetyl CoA from the mitochondria to the cytosol.
  - Mitochondrial acetyl CoA reacts with oxaloacetate to produce citrate.
  - Citrate is transported through the inner mitochondrial membrane.
  - In the cytosol, citrate regenerates acetyl CoA and oxaloacetate.
  - The acetyl CoA generated is the fuel for lipogenesis.
ACP Complex Formation:
- All intermediates in fatty acid biosynthesis (lipogenesis) are bound to acyl carrier proteins (ACP-SH; giant coenzyme A).
- Involved in the ACP structure are the 2-ethanethiol and pantothenic acid components present in CoA-SH, which are attached to a polypeptide chain containing 77 amino acid residues.
- Two ACP complexes are needed to start the lipogenesis process: acetyl ACP and malonyl ACP.
- Acetyl ACP is produced by the direct reaction of acetyl CoA with an ACP molecule.
Chain Elongation involves Four Reactions :
- ** Step 1: Condensation**
  - Acetyl ACP and malonyl ACP condense together to form acetoacetyl ACP.
    - $\text{Acetyl ACP} + \text{ Malonyl ACP} \rightarrow \text{Acetoacetyl ACP} + CO_2 + ACP$
- Step 2: First hydrogenation
  - The keto group of the acetoacetyl complex, which involves the β-carbon atom, is reduced to the corresponding alcohol by NADPH.
    - $\text{Acetoacetyl ACP} + NADPH + H^+ \rightarrow \beta\text{-Hydroxybutyryl ACP} + NADP^+$
- Step 3: Dehydration
  - The alcohol produced in Step 2 is dehydrated to introduce a double bond into the molecule (between the α and β carbons)
    - $\beta\text{-Hydroxybutyryl ACP} \rightarrow \text{Crotonyl ACP} + H_2O$
- Step 4: Second hydrogenation.
  - The double bond introduced in Step 3 is converted to a single bond through hydrogenation. As in Step 2, NADPH is the reducing agent.
    - $\text{Crotonyl ACP} + NADPH + H^+ \rightarrow \text{Butyryl ACP} + NADP^+$
Chain elongation stops upon formation of the C16 acyl group (palmitic acid).
Different enzyme systems and different cellular locations are required for elongation of the chain beyond C16 and for introduction of double bonds into the acyl group (unsaturated fatty acids).
Table 25.2 Reactants and Products in the Biosynthesis of One Molecule of Palmitic Acid, the 16:0 Fatty Acid
- Reactants: 8 acetyl CoA, 7 ATP, 14 NADPH
- Products: 1 palmitate, 8 CoA, 7 ADP, 6 H+, 7 Pi, 14 NADP+, 6 H2O
Unsaturated Fatty Acid Biosynthesis:
- Requires molecular oxygen (O2).
- Enzymes can introduce double bonds only between C-4 and C-5 and between C-9 and C-10 in humans and animals.
- Acids such as linoleic and linolenic, which cannot be synthesized by the body but are necessary for its proper functioning, are called essential fatty acids.

25.8 Relationships Between Lipogenesis and Citric Acid Cycle Intermediates

The intermediates in the last four steps of the citric acid cycle are all C4 molecules.
In the first cycle of the four repetitive reactions in lipogenesis all of the carbon chains attached to ACP are C4 chains.
The last four intermediates of the citric acid cycle bear the following relationship to each other:
- Saturated C4 diacid ⇄ unsaturated C4 diacid ⇄ hydroxy C4 diacid ⇄ keto C4 diacid
- The intermediate C4 carbon chains of lipogenesis bear the following relationship to each other:
- Keto C4 monoacid ⇄ hydroxy C4 monoacid ⇄ unsaturated C4 monoacid ⇄ saturated C4 monoacid

25.9 Biosynthesis of Cholesterol

Every membrane of every cell in the body has cholesterol as a necessary component.
Substance is also the precursor for bile salts, sex hormones, and adrenal hormones
Average daily dietary intake of cholesterol is approximately 0.3 gram.
The biosynthesis of cholesterol, a C27 molecule, occurs primarily in the liver.
Its production consumes 18 molecules of acetyl CoA and involves at least 27 separate enzymatic steps.
Cholesterol is biosynthesized from acetyl CoA in a complex series of reactions in which isoprene units are key intermediates.
Phases of Cholesterol Biosynthesis:
- Phase 1: Three molecules of acetyl CoA are condensed into a C6 mevalonate ion.
  - $3 \text{ Acetyl CoA} \rightarrow \text{Mevalonate}$
- Phase 2: The C6 mevalonate undergoes a decarboxylation to yield a C5 isoprene derivative called isopentenyl pyrophosphate and CO2.
  - $\text{Mevalonate} \rightarrow \text{Isopentenyl pyrophosphate} + CO_2$
- Phase 3: Six isoprene units are condensed to give the C30 squalene molecule.
- Phase 4: The squalene transitions to lanosterol involves the formation of four ring systems, a decrease in double bonds from six to two, the migration of two methyl groups to new locations, and the addition of an —OH group to the C30 system
- Phase 5: The transition from lanosterol to cholesterol involves removal of three methyl groups (C30 to C27), reduction of the double bond in the side chain, and migration of the other double bond to a new location.
CHEMICAL CONNECTIONS: Statins: Drugs That Lower Plasma Levels of Cholesterol
- Statins are drugs used to lower plasma concentrations of LDL by functioning as competitive inhibitors of HMG-CoA reductase.
Biosynthetic pathways are available to convert cholesterol to each of the five major classes of steroid hormones: progestins, androgens, estrogens, glucocorticoids, and mineralocorticoids

25.10 Relationships Between Lipid and Carbohydrate Metabolism

Acetyl CoA is the primary link between lipid and carbohydrate metabolism.
Acetyl CoA is the degradation product for glucose, glycerol, and fatty acids, and it is also the starting material for the biosynthesis of fatty acids, cholesterol, and ketone bodies.
Four Possible Fates of Acetyl CoA:
- Oxidation in the citric acid cycle.
- Ketone body formation.
- Fatty acid biosynthesis.
- Cholesterol biosynthesis.