Nov 24, 2025 PDF Available

Topic Overview

⭐ Digestion of Medium-Chain Fatty Acids (MCFAs)

Medium-chain fatty acids (MCFAs) are fatty acids containing 6–12 carbon atoms. Their digestion is simpler, faster, and more efficient than long-chain fatty acids (LCFAs), and this gives them distinct metabolic features.

⭐ Characteristics of Medium-Chain Fatty Acids

Water-soluble compared to long-chain fatty acids
Do not require bile salts for digestion
Do not need micelle formation
Absorbed directly into portal circulation
Used rapidly for energy, less likely to be stored as fat

Common examples include caproic (C6), caprylic (C8), capric (C10), lauric acid (C12).

⭐ Process of Digestion

⭐ 1. In the Stomach

Minimal digestion occurs.
Gastric lipase can act on milk fat (important in infants) but plays a minor role in adults.

⭐ 2. In the Small Intestine

Unlike long-chain fatty acids:

Medium-chain fatty acids do NOT require:

Bile salt emulsification
Pancreatic lipase activation
Micelle formation

Why?

Their smaller size makes them naturally water-soluble, allowing them to diffuse without complex processing.

⭐ 3. Absorption into Enterocytes

MCFAs cross the intestinal epithelial membrane directly by simple diffusion.
Unlike LCFAs, they are not re-esterified into triglycerides inside the enterocyte.

⭐ 4. Transport After Absorption

MCFAs bind to albumin in the portal blood.
Directly transported to the liver via the portal vein.
Do not require formation of chylomicrons.
Do not enter lymphatic circulation.

⭐ Metabolic Fate in Liver

Once delivered to liver:

Rapidly undergo β-oxidation
Quickly generate ATP
Used during fasting, exercise, or ketogenic diets
Rarely stored as adipose fat
Do not require carnitine for mitochondrial entry, unlike long-chain fatty acids

This is why MCT oil is used in:

Malabsorption syndromes
Ketogenic diets
Premature infants
Patients with pancreatic insufficiency

⭐ Clinical Significance

Useful in fat malabsorption (celiac disease, chronic pancreatitis).
Useful in cholecystectomy patients because they do not need bile salts.
Pregnant and breastfeeding women sometimes use MCT oil to increase energy availability.
In mitochondrial disorders, MCFAs offer a rapid energy source.

⭐ Monounsaturated Fatty Acids (MUFA)

Monounsaturated fatty acids contain one double bond in the hydrocarbon chain.

⭐ Common MUFAs

Oleic acid (18:1, Δ9) — most abundant MUFA in human diet
Palmitoleic acid (16:1, Δ9)
Gadoleic acid (20:1)

⭐ Sources

Olive oil
Groundnut oil
Avocado
Nuts
Almonds
Sesame oil

⭐ Structure and Properties

One cis double bond creates a “kink,” lowering melting point.
Liquid at room temperature, unlike saturated fat.
More stable than polyunsaturated fatty acids → less prone to oxidation.

⭐ Functions of MUFAs

Improve insulin sensitivity
Lower LDL cholesterol without reducing HDL
Provide membrane fluidity
Serve as precursors for neutral lipids and phospholipids
Reduce oxidative stress and inflammation
Preferred cooking oils due to high oxidative stability

⭐ Clinical Importance

Diets rich in MUFAs (e.g., Mediterranean diet) reduce risk of:
- Cardiovascular disease
- Atherosclerosis
- Metabolic syndrome
- Type 2 diabetes
Oleic acid improves endothelial function and reduces systemic inflammation.

⭐ β-Oxidation of Unsaturated Fatty Acids

Unsaturated fatty acids undergo β-oxidation with additional steps, because double bonds disrupt the regular β-oxidation spiral.

β-Oxidation normally requires a trans-Δ²-enoyl CoA intermediate, but natural double bonds are cis and may be at odd or even positions.
So, auxiliary enzymes are needed.

⭐ Case 1: Oxidation of Monounsaturated Fatty Acids

Example: Oleic acid (18:1, Δ9, cis)

After several rounds of β-oxidation, the double bond eventually appears at position 3 (Δ³-cis).

⭐ Problem

β-oxidation machinery cannot handle cis-Δ³ double bond.

⭐ Solution: Enoyl-CoA Isomerase

The enzyme Enoyl-CoA isomerase converts:

cis-Δ³-enoyl CoA → trans-Δ²-enoyl CoA

This intermediate enters the normal β-oxidation cycle.

⭐ Energy Yield

Monounsaturated fatty acids produce slightly less ATP than saturated fatty acids of the same length because one FADH₂-producing step is skipped (double bond bypasses the first dehydrogenation step).

⭐ Case 2: Oxidation of Polyunsaturated Fatty Acids (PUFA)

(A preview for the next heading)

PUFAs require:

Enoyl-CoA isomerase
2,4-Dienoyl-CoA reductase
to handle conjugated double bonds.

I will expand fully when we reach PUFA.

⭐ Combined Flow (β-Oxidation of Unsaturated Fatty Acids)

Unsaturated FA → β-oxidation begins normally ↓ Encounter cis double bond ↓ If cis-Δ³ → Enoyl-CoA Isomerase → trans-Δ² → β-oxidation continues ↓ (For PUFA) Conjugated double bond → 2,4-Dienoyl-CoA reductase → Enoyl-CoA Isomerase ↓ Normal β-oxidation

⭐ Clinical Significance

Deficiency of Enoyl-CoA Isomerase leads to accumulation of unsaturated fatty acyl intermediates and impaired lipid oxidation.
Disorders of PUFA oxidation can contribute to:
- Exercise intolerance
- Hypoketotic hypoglycemia
- Mitochondrial β-oxidation defects
Fatty acid oxidation disorders require high-carbohydrate diets and avoidance of fasting.

⭐ Polyunsaturated Fatty Acids (PUFA)

Polyunsaturated fatty acids contain two or more double bonds in their hydrocarbon chain.

These double bonds are almost always in the cis configuration, producing a kinked, flexible structure essential for membrane function.

⭐ Common PUFAs

Omega-6 (n-6) family

Linoleic acid (18:2, Δ9,12) — Essential
Arachidonic acid (20:4, Δ5,8,11,14) — precursor of prostaglandins

Omega-3 (n-3) family

α-Linolenic acid (18:3, Δ9,12,15) — Essential
EPA (20:5)
DHA (22:6)

Humans cannot synthesize linoleic and α-linolenic acids; hence they are essential.

⭐ Functions of PUFAs

Maintain membrane fluidity (especially neuronal membranes)
Essential for brain and retinal development (DHA)
Precursors for eicosanoids:
- Prostaglandins
- Thromboxanes
- Leukotrienes
Regulate inflammatory responses
Decrease triglycerides
Improve cardiovascular health
Omega-3 reduces platelet aggregation

⭐ Health Benefits

Omega-3

Anti-inflammatory
Anti-thrombotic
Improves endothelial function
Reduces risk of coronary artery disease

Omega-6

Required for growth, skin integrity
Excess omega-6 without omega-3 → pro-inflammatory

Balanced omega-6 : omega-3 ratio (ideal ≈ 4:1) is important.

⭐ Sources of PUFAs

Omega-6

Sunflower oil
Corn oil
Soybean oil
Nuts and seeds

Omega-3

Fish oil (EPA, DHA)
Flaxseed
Chia seeds
Walnuts
Mustard oil

⭐ Deficiency Features

Scaly dermatitis
Poor wound healing
Reduced immunity
Growth retardation
Neurological defects in infants (DHA deficiency)

⭐ Metabolism of PUFAs (Overview)

Essential fatty acids → elongated & desaturated in the ER to produce long-chain PUFAs like:

Arachidonic acid
EPA
DHA

These then serve as substrates for eicosanoid synthesis.

⭐ Desaturation of Fatty Acids

Desaturation means introducing double bonds into a saturated fatty acid.

This occurs in the smooth endoplasmic reticulum.

⭐ Key Features

Requires O₂, NADH, Cytochrome b5, and desaturase enzyme.
Each reaction introduces one double bond.
Humans have Δ9, Δ6, Δ5, and Δ4 desaturases.

⭐ Why Some Fatty Acids Are Essential?

Humans cannot introduce double bonds beyond carbon 9 from the carboxyl end.

So we cannot synthesize:

Linoleic acid (Δ9,12)
α-Linolenic acid (Δ9,12,15)

These must be obtained from diet → essential fatty acids.

⭐ Desaturation Reaction (Simplified)

Saturated FA + O₂ + NADH → Unsaturated FA + H₂O + NAD⁺

Cytochrome b5 and Cytochrome-b5 reductase are required.

⭐ Sequence of Desaturation + Elongation

Example: Synthesis of arachidonic acid (20:4)

Linoleic acid (18:2)

↓ (Δ6 desaturase)

Gamma-linolenic acid (18:3)

↓ (elongase)

Dihomo-gamma-linolenic acid (20:3)

↓ (Δ5 desaturase)

Arachidonic acid (20:4)

⭐ Clinical Points

Δ6 desaturase activity declines in diabetes, aging, alcoholism → low PUFA levels
DHA deficiency affects cognitive development in infants
PUFA deficiency leads to scaly dermatitis
Excess omega-6 increases inflammatory mediators (prostaglandins, leukotrienes)

⭐ Ultra-Short Revision

PUFA = ≥2 double bonds; essential ones: linoleic (ω-6), α-linolenic (ω-3).
Required for brain, retina, membrane fluidity.
Omega-3 = anti-inflammatory, omega-6 = pro-inflammatory in excess.
Humans lack Δ12 & Δ15 desaturases, making essential FA obligatory in diet.
Desaturation occurs in ER, requires O₂, NADH, cytochrome b5.

⭐ Polyunsaturated Fatty Acids (PUFA)

Polyunsaturated fatty acids contain two or more cis double bonds. These bends caused by cis bonds make membranes flexible and biologically active.

⭐ Essential PUFAs

Humans cannot introduce double bonds beyond carbon 9, so two fatty acids are essential:

Linoleic acid (18:2, ω-6)
α-Linolenic acid (18:3, ω-3)

All other long-chain PUFAs are made from these.

⭐ Important PUFA Families

Omega-6 Series

Linoleic acid → Arachidonic acid (20:4)
Arachidonic acid is the main substrate for prostaglandins, thromboxanes, and leukotrienes.

Omega-3 Series

α-Linolenic acid → EPA (20:5) → DHA (22:6)
DHA is crucial for brain, retina, and fetal development.

⭐ Functions of PUFAs

Maintain membrane fluidity, especially neurons
Essential for brain growth and retinal function
Form eicosanoids (prostaglandins, thromboxanes, leukotrienes)
Reduce plasma triglycerides
Omega-3 reduces inflammation and platelet aggregation
Required for skin barrier and wound healing

⭐ Sources

Omega-6: Sunflower oil, safflower oil, soybean, nuts
Omega-3: Fish oil, flaxseed, chia, walnuts, mustard oil

⭐ Deficiency

Scaly dermatitis
Poor wound healing
Growth failure
Infertility
Reduced immunity
Poor visual development (DHA deficiency)

⭐ Clinical Notes

Excess omega-6 without omega-3 → pro-inflammatory state
Balanced ratio (~4:1) is important
PUFA deficiency resembles essential fatty acid deficiency syndrome

⭐ Desaturation of Fatty Acids

Desaturation is the process of introducing double bonds into saturated fatty acids.
This occurs in the smooth endoplasmic reticulum (SER).

⭐ Desaturase Enzymes in Humans

Humans have the following desaturases:

Δ9 desaturase
Δ6 desaturase
Δ5 desaturase
Δ4 desaturase

Each enzyme introduces one double bond.

⭐ Why Essential Fatty Acids Are Essential

Humans lack Δ12 and Δ15 desaturases, so we cannot make:

Linoleic acid (Δ9,12)
α-Linolenic acid (Δ9,12,15)

These must be taken from diet → Essential Fatty Acids.

⭐ Requirements for Desaturation

Desaturation requires:

FAD → FADH₂
NADH → NAD⁺
Cytochrome b₅
Cytochrome b₅ reductase
Oxygen (O₂)

One oxygen atom becomes part of water, the other inserted as the new double bond.

⭐ Desaturation Reaction (Simplified)

Saturated acyl-CoA + NADH + O₂

↓ Desaturase

Unsaturated acyl-CoA + NAD⁺ + H₂O

⭐ Example: Making Arachidonic Acid

From dietary linoleic acid:

Linoleic acid (18:2)

↓ Δ6 desaturase

γ-Linolenic acid (18:3)

↓ Elongase

Dihomo-γ-linolenic acid (20:3)

↓ Δ5 desaturase

Arachidonic acid (20:4)

⭐ Clinical Importance

Δ6 desaturase decreases with age, diabetes, alcohol
Leads to reduced EPA/DHA production
Infants, especially premature, need dietary DHA
Disorders of desaturation contribute to inflammatory and neurological problems

⭐ High-Yield Summary

PUFA = ≥2 cis double bonds; essential ones: linoleic (ω-6), α-linolenic (ω-3)
Omega-3 → anti-inflammatory; Omega-6 → pro-inflammatory if excess
Humans cannot desaturate beyond C9, hence essential fatty acids
Desaturation occurs in SER, requires NADH, Cytochrome b₅, and O₂

⭐ Essential Fatty Acids (EFA)

Essential fatty acids are fatty acids that cannot be synthesized by humans because we lack Δ12 and Δ15 desaturase enzymes.
Therefore, double bonds cannot be introduced beyond carbon 9.

⭐ The Essential Fatty Acids

1. Linoleic Acid (18:2, ω-6)

Precursor of arachidonic acid (20:4)
Required for prostaglandin synthesis
Maintains skin integrity

2. α-Linolenic Acid (18:3, ω-3)

Precursor of EPA (20:5) and DHA (22:6)
Important for brain, retina, neural development

⭐ Functions of EFAs

Maintain membrane fluidity
Essential for brain and retinal development (DHA)
Required for skin barrier, preventing eczema
Precursors for eicosanoids
Reduce serum triglycerides (especially omega-3)
Influence inflammatory and immune responses

⭐ Deficiency Features

Dry, scaly dermatitis
Poor wound healing
Growth retardation
Infertility
Reduced immunity
Neurological defects (DHA deficiency in infants)

⭐ Eicosanoids

Eicosanoids are short-lived, highly potent, hormone-like molecules derived from 20-carbon PUFAs—mainly arachidonic acid (20:4).

They include:

Prostaglandins (PGs)
Thromboxanes (TXs)
Leukotrienes (LTs)
Lipoxins

They act as local mediators (autocrine/paracrine).

⭐ Sources of Eicosanoids

Arachidonic acid (omega-6)
EPA (omega-3) → produces “less inflammatory” eicosanoids

⭐ Pathways

1. Cyclooxygenase (COX) Pathway → Prostaglandins + Thromboxanes

Enzymes: COX-1 and COX-2

2. Lipoxygenase (LOX) Pathway → Leukotrienes + Lipoxins

Enzyme: 5-Lipoxygenase

⭐ Prostaglandins

Prostaglandins (PGs) are produced from the COX pathway.

⭐ Precursor

Arachidonic acid → PGG₂ → PGH₂ → various PGs (PGE₂, PGF₂α, PGI₂, etc.)

⭐ Types & Functions

1. PGE₂ – “Inflammatory Prostaglandin”

Fever (acts on hypothalamus)
Pain sensitivity
Vasodilation
Uterine contractions
Protects gastric mucosa

2. PGI₂ (Prostacyclin) – “Platelet Protector”

Formed by vascular endothelium
Vasodilation
Inhibits platelet aggregation
Opposes TXA₂

3. TXA₂ (Thromboxane A₂) – “Platelet Activator”

Formed by platelets
Vasoconstriction
Promotes platelet aggregation
Opposes PGI₂

4. PGF₂α

Uterine contraction
Used clinically to induce labor or abortion
Vasoconstriction in some tissues

⭐ Clinical Points (Prostaglandins)

NSAIDs (aspirin, ibuprofen) inhibit COX → ↓ PG synthesis
Low-dose aspirin inhibits platelet TXA₂ → anti-thrombotic
COX-2 inhibitors (celecoxib) spare gastric mucosa (COX-1 preserved)

⭐ Leukotrienes

Leukotrienes are formed via the 5-lipoxygenase (LOX) pathway.

⭐ Precursor

Arachidonic acid → 5-HPETE → LTA₄

LTA₄ gives rise to two pathways:

LTB₄
LTC₄ → LTD₄ → LTE₄

⭐ Functions

1. LTB₄ – Neutrophil Activator

Chemotaxis
Neutrophil adhesion
Superoxide production
Strong inflammatory mediator

2. LTC₄, LTD₄, LTE₄ – Bronchoconstrictors (Slow Reacting Substances of Anaphylaxis)

Potent bronchoconstriction
Increase vascular permeability
Mucus hypersecretion
Major role in asthma and allergic reactions

⭐ Clinical Relevance (Leukotrienes)

Montelukast / Zafirlukast → Block LTD₄ receptor → used in asthma
Zileuton → inhibits 5-LOX → decreases all leukotrienes

⭐ Ultra-Short Revision Points

EFAs = linoleic (ω-6) & α-linolenic (ω-3).
Arachidonic acid → main precursor of eicosanoids.
Eicosanoids act locally (autocrine/paracrine).
COX pathway → PGs + TXA₂.
LOX pathway → Leukotrienes.
TXA₂ = platelet aggregation; PGI₂ = anti-aggregation.
LTB₄ = neutrophil chemotaxis; LTC₄/LTD₄ = bronchoconstriction.
NSAIDs block COX; montelukast blocks LTD₄ receptor.

⭐ Very Long Chain Fatty Acids (VLCFA)

Very long chain fatty acids are fatty acids with more than 22 carbon atoms.
Examples include:

Lignoceric acid (24:0)
Cerotic acid (26:0)

They have crucial roles in nervous system structure and membrane integrity.

⭐ Where Are VLCFAs Found?

Myelin sheath of neurons
Retina
Testes
Skin barrier lipids
Sphingolipids (e.g., cerebrosides & sphingomyelin)

⭐ Metabolism of VLCFAs

⭐ Synthesis

Occurs in endoplasmic reticulum via elongation of long-chain fatty acids
Uses elongase enzymes and malonyl-CoA for adding 2-carbon units

⭐ Oxidation

VLCFAs cannot enter mitochondria
They undergo β-oxidation in peroxisomes, not mitochondria

Process:

VLCFA transported into peroxisome
Shortened through peroxisomal β-oxidation
Once shortened to C16–C20 → shifted to mitochondria for further oxidation

⭐ Clinical Points (VLCFA Disorders)

⭐ 1. X-Linked Adrenoleukodystrophy (X-ALD)

Defect in peroxisomal membrane transporter (ABCD1 gene)
VLCFAs accumulate in:
- Brain white matter
- Adrenal cortex
Leads to:
- Progressive neurological deterioration
- Adrenal insufficiency

⭐ 2. Zellweger Syndrome

Peroxisome biogenesis disorder
VLCFA accumulate because peroxisomes cannot function
Severe hypotonia, seizures, craniofacial abnormalities

⭐ 3. Refsum Disease

Disorder of α-oxidation (phytanic acid metabolism)
Not VLCFA directly, but associated with similar peroxisomal pathways

⭐ Why VLCFAs Require Peroxisomes?

Their chains are too long to be handled by mitochondrial carnitine shuttle
Peroxisomes start the process, then mitochondria finish the oxidation

⭐ Key Points to Remember

VLCFA = >22 carbons
Oxidized in peroxisomes, not mitochondria
Defects → severe neurological diseases due to myelin damage
Abnormal accumulation is a hallmark of X-ALD and Zellweger syndrome

⭐ Synthesis of Compound Lipids

Compound lipids are lipids that contain fatty acids + alcohol + an additional group (phosphate, carbohydrate, etc.).

They include:

Phospholipids
Glycolipids (cerebrosides, gangliosides)
Sphingolipids
Plasmalogens

⭐ 1. Synthesis of Phospholipids

Phospholipids contain:

Glycerol backbone
Two fatty acids
Phosphate group + head group (choline, ethanolamine, serine, inositol)

⭐ Synthesis Pathway (Glycerophospholipids)

⭐ Step 1: Formation of Phosphatidic Acid

Glycerol-3-phosphate + 2 Fatty acyl-CoA

↓ Acyltransferases

Phosphatidic acid (PA)

⭐ Step 2: Conversion to CDP-Activated Intermediates

Two possible routes:

Route A:

PA + CTP → CDP-diacylglycerol

Used to form:

Phosphatidylinositol
Cardiolipin
Phosphatidylglycerol

Route B:

Choline/Ethanolamine + ATP → CDP-choline / CDP-ethanolamine

Combined with DAG to form:

Phosphatidylcholine (lecithin)
Phosphatidylethanolamine

⭐ 2. Synthesis of Sphingolipids

Sphingolipids use sphingosine instead of glycerol.

⭐ Step 1: Formation of Sphingosine

Serine + Palmitoyl-CoA

↓

Sphinganine → Sphingosine

⭐ Step 2: Formation of Ceramide

Sphingosine + Fatty acyl-CoA → Ceramide

⭐ Step 3: Formation of Complex Sphingolipids

Ceramide + Phosphocholine → Sphingomyelin
Ceramide + Sugar → Cerebroside
Ceramide + Oligosaccharide → Ganglioside

⭐ 3. Synthesis of Glycolipids

⭐ Cerebrosides

Ceramide + UDP-sugar → Cerebroside

Glucocerebroside
Galactocerebroside

⭐ Gangliosides

Ceramide + multiple sugars + sialic acid (NANA) → Ganglioside

Highly important in neuronal membranes.

⭐ 4. Synthesis of Plasmalogens

These contain a vinyl-ether linkage at position 1 of glycerol.

Precursor: Dihydroxyacetone phosphate (DHAP)

Plasmalogens act as:

Antioxidants
Membrane components in nerve & muscle

⭐ Clinical Relevance of Compound Lipid Synthesis

Gaucher disease: glucocerebrosidase deficiency
Tay–Sachs disease: hexosaminidase A deficiency → GM₂ accumulation
Niemann–Pick: sphingomyelinase deficiency
Multiple sclerosis: loss of myelin sphingolipids

⭐ Ultra-High-Yield Summary

VLCFA (>22C) → oxidized only in peroxisomes.
Peroxisome disorders → accumulation and neurological disease.
Compound lipids include phospholipids, glycolipids, sphingolipids, plasmalogens.
Ceramide is the central precursor for sphingolipids.
Phospholipids synthesized via CDP-choline, CDP-ethanolamine, and CDP-DAG pathways.

⭐ Phosphatidylcholine (Lecithin)

Phosphatidylcholine (PC) is the most abundant phospholipid in cell membranes and plasma lipoproteins.
It plays major roles in membrane structure, lung function, and lipid transport.

⭐ Structure

Glycerol backbone
Two fatty acids (usually saturated at C1, unsaturated at C2)
Phosphate
Choline head group

⭐ Synthesis of Phosphatidylcholine

1. CDP–Choline Pathway (Kennedy Pathway) — Major in most tissues

Choline + ATP → Phosphocholine

Phosphocholine + CTP → CDP–choline

CDP–choline + DAG → Phosphatidylcholine

2. PEMT Pathway (Liver only)

Phosphatidylethanolamine → methylated three times using SAM → PC
This pathway is important when dietary choline is low.

⭐ Functions of Phosphatidylcholine

1. Structural role

Major phospholipid of cell membranes
Maintains membrane fluidity

2. Lung Surfactant

Dipalmitoyl phosphatidylcholine (DPPC) is the key surfactant component
Prevents alveolar collapse
Low levels → neonatal respiratory distress syndrome (RDS)

3. Lipoprotein Metabolism

Essential for VLDL formation and secretion
Prevents fatty liver (choline deficiency → hepatic steatosis)

4. Bile Component

Solubilizes cholesterol in bile
Prevents gallstone formation

⭐ Clinical Notes

Choline deficiency → fatty liver
Premature infants have low DPPC → high risk of RDS
Lecithin:Sphingomyelin ratio in amniotic fluid predicts fetal lung maturity
(L/S ratio > 2 = mature lungs)

⭐ Sphingomyelin

Sphingomyelin is the major sphingophospholipid, abundant in myelin sheath.

⭐ Structure

Sphingosine backbone
Fatty acid (amide linkage) → Ceramide
Phosphocholine head group

Sphingomyelin = Ceramide + Phosphocholine

⭐ Synthesis of Sphingomyelin

Serine + Palmitoyl-CoA → Sphinganine

Sphinganine + Fatty acyl-CoA → Ceramide

Ceramide + CDP–choline → Sphingomyelin

Occurs in the Golgi apparatus.

⭐ Functions of Sphingomyelin

Major component of myelin (nerve insulation)
Important in signal transduction
Component of lipid rafts
Regulates cell–cell interactions
Maintains plasma membrane stability

⭐ Clinical Note: Niemann–Pick Disease (Type A & B)

Deficiency: Sphingomyelinase
Accumulation: Sphingomyelin
Features:

Hepatosplenomegaly
Cherry-red spot on macula
Neurodegeneration (Type A)
“Foam cells” in bone marrow

⭐ Lipid Storage Diseases (Sphingolipidoses)

Lipid storage diseases result from defects in lysosomal enzymes → accumulation of specific sphingolipids.

⭐ 1. Gaucher Disease

Deficiency: β-Glucocerebrosidase
Accumulation: Glucocerebroside
Features:

Hepatosplenomegaly
Bone crises
Pancytopenia
“Gaucher cells” — crumpled tissue paper macrophages
Most common lysosomal storage disorder

⭐ 2. Niemann–Pick Disease (Type A/B)

Deficiency: Sphingomyelinase
Accumulation: Sphingomyelin
Features:

Cherry-red spot
Neurodegeneration
Hepatosplenomegaly
Foam cells

⭐ 3. Tay–Sachs Disease

Deficiency: Hexosaminidase A
Accumulation: GM₂ ganglioside
Features:

Cherry-red spot
No hepatosplenomegaly
Severe neurodegeneration
Startle reflex exaggerated

⭐ 4. Krabbe Disease

Deficiency: Galactocerebrosidase
Accumulation: Galactocerebroside, psychosine
Features:

Peripheral neuropathy
Optic atrophy
Developmental delay
Globoid cells

⭐ 5. Metachromatic Leukodystrophy

Deficiency: Arylsulfatase A
Accumulation: Sulfatides
Features:

Ataxia
Demyelination
Peripheral neuropathy
Cognitive decline
“Metachromasia” on staining

⭐ 6. Fabry Disease

Inheritance: X-linked
Deficiency: α-Galactosidase A
Accumulation: Ceramide trihexoside
Features:

Angiokeratomas
Peripheral neuropathy
Hypohidrosis
Renal and cardiac involvement

⭐ 7. Farber Disease

Deficiency: Ceramidase
Accumulation: Ceramide
Features:

Hoarseness
Joint deformity
Subcutaneous nodules

⭐ 8. Pompe Disease (not a sphingolipidosis, but a glycogen storage disorder often grouped in lysosomal diseases)

Deficiency: Acid maltase
Effect: Glycogen accumulation in lysosomes
Features: Cardiomyopathy, hypotonia

⭐ Ultra-High-Yield Summary

Phosphatidylcholine = major membrane lipid + surfactant + VLDL assembly
Sphingomyelin = major myelin phospholipid; defect → Niemann–Pick
Lipid storage diseases → enzyme defect → specific lipid accumulation
- Gaucher → glucocerebroside
- Tay–Sachs → GM₂
- Krabbe → galactocerebroside
- Metachromatic → sulfatides
- Fabry → ceramide trihexoside
- Niemann–Pick → sphingomyelin

⭐ FAQs — Phosphatidylcholine, Sphingomyelin & Lipid Storage Diseases

1. What is phosphatidylcholine?

It is the most abundant phospholipid in cell membranes and lipoproteins; also known as lecithin.

2. What is the key component of lung surfactant?

Dipalmitoyl phosphatidylcholine (DPPC).

3. What is the L/S ratio and why is it important?

Lecithin : Sphingomyelin ratio in amniotic fluid.
L/S > 2 indicates fetal lung maturity.

4. What happens in phosphatidylcholine deficiency?

Liver cannot export VLDL → fatty liver (hepatic steatosis).

5. How is phosphatidylcholine synthesized in most tissues?

Via the CDP–choline (Kennedy) pathway.

6. Which tissue can synthesize PC without dietary choline?

Liver, via methylation of phosphatidylethanolamine (PEMT pathway).

7. What is sphingomyelin?

A phospholipid containing ceramide + phosphocholine, abundant in myelin sheaths.

8. What is the key precursor for both sphingomyelin and glycolipids?

Ceramide.

9. Which enzyme deficiency causes Niemann–Pick disease?

Sphingomyelinase.

10. What accumulates in Niemann–Pick disease?

Sphingomyelin.

11. What are the typical findings in Niemann–Pick disease?

Hepatosplenomegaly, neurodegeneration, cherry-red spot, foam cells.

12. What accumulates in Gaucher disease?

Glucocerebroside.

13. What is the enzyme deficient in Gaucher disease?

β-Glucocerebrosidase.

14. What is the histological hallmark of Gaucher disease?

Gaucher cells — macrophages with “crumpled tissue paper” cytoplasm.

15. Which storage disease presents with a cherry-red spot but NO hepatosplenomegaly?

Tay–Sachs disease.

16. What accumulates in Tay–Sachs disease?

GM₂ ganglioside.

17. What enzyme is deficient in Tay–Sachs?

Hexosaminidase A.

18. What accumulates in Krabbe disease?

Galactocerebroside and psychosine.

19. What is the deficient enzyme in Krabbe disease?

Galactocerebrosidase.

20. What accumulates in Metachromatic leukodystrophy?

Sulfatides.

21. Which enzyme is deficient in Metachromatic leukodystrophy?

Arylsulfatase A.

22. What accumulates in Fabry disease?

Ceramide trihexoside.

23. What is the inheritance pattern of Fabry disease?

X-linked recessive.

24. What is the enzyme deficient in Fabry disease?

α-Galactosidase A.

25. What is the typical presentation of Fabry disease?

Angiokeratomas, peripheral neuropathy, hypohidrosis, renal/cardiac involvement.

26. What accumulates in Farber disease?

Ceramide.

27. What enzyme is deficient in Farber disease?

Ceramidase.

28. Which storage diseases show a cherry-red spot?

Tay–Sachs
Niemann–Pick

29. Which disease presents with “globoid cells”?

Answer: B
(Defect → Refsum disease)

30. Arachidonic acid belongs to which series?

A. Omega-3
B. Omega-6
C. Omega-9
D. Trans fatty acids

Answer: B

Alcohol ↑ NADH, inhibiting β-oxidation → excess TAG formation in liver.

17. Asthma well-controlled with Montelukast

A young woman responds dramatically to Montelukast.

Mechanism:

Montelukast blocks LTD₄ receptor, preventing leukotriene-mediated bronchoconstriction.

18. Patient with abnormal bleeding & platelet dysfunction

Low prostacyclin and thromboxane levels.

Most likely enzyme inhibited:

Cyclooxygenase (COX) by aspirin → ↓ TXA₂ & PGI₂ synthesis.

19. Adult with fat malabsorption; long-chain fats worsen symptoms

Patient improves when diet includes medium-chain triglycerides.

Reason:

MCFA bypass:

bile
micelles
chylomicrons
→ directly absorbed to portal vein.

20. Child with scaly dermatitis and growth delay

Diet low in vegetable oils, fish, nuts.

Deficiency:

Essential fatty acids (linoleic & α-linolenic)

Mechanism:

Defective skin barrier & eicosanoid production.

⭐ Viva Voce — Whole Chapter

1. What is the special feature of medium-chain fatty acids?

They do not require bile salts or micelles and are absorbed directly into portal circulation.

2. Why do MCFAs not need chylomicrons?

They are water-soluble and travel bound to albumin.

3. What is the key difference between MUFA and PUFA?

MUFA have one double bond, PUFA have two or more.

4. Name the two essential fatty acids.

Linoleic acid (ω-6) and α-linolenic acid (ω-3).

5. Why are these fatty acids essential?

Humans lack Δ12 and Δ15 desaturase enzymes.

6. What is the precursor of arachidonic acid?

Linoleic acid (ω-6).

7. What are the major omega-3 derivatives?

EPA and DHA.

8. Which fatty acid is crucial for retinal and brain development?

DHA.

9. What enzyme releases arachidonic acid from membranes?

Phospholipase A₂.

10. Which pathways convert arachidonic acid to eicosanoids?

COX pathway and LOX pathway.

11. What does COX produce?

Prostaglandins and Thromboxanes.

12. What does 5-Lipoxygenase (LOX) produce?

Leukotrienes (LTB₄, LTC₄, LTD₄, LTE₄).

13. What is the action of LTB₄?

Strong neutrophil chemotaxis.

14. Which leukotrienes cause bronchoconstriction?

LTC₄, LTD₄, LTE₄.

15. What drug blocks leukotriene receptors?

Montelukast.

16. What enzyme is inhibited by aspirin?

COX-1 and COX-2.

17. What is PGI₂? Where is it produced?

Prostacyclin, produced by endothelium.
It inhibits platelet aggregation.

18. What is TXA₂? Where is it produced?

Thromboxane A₂, produced by platelets.
It promotes aggregation.

19. What are very long-chain fatty acids (VLCFA)?

Fatty acids with >22 carbons.

20. Where are VLCFAs oxidized?

In peroxisomes.

21. Which disease involves VLCFA accumulation?

X-linked adrenoleukodystrophy (ALD).

22. Name the major lung surfactant component.

Dipalmitoyl phosphatidylcholine (DPPC).

23. What is the L/S ratio?

Lecithin : Sphingomyelin ratio.
>2 indicates fetal lung maturity.

24. What happens in phosphatidylcholine deficiency?

Impaired VLDL secretion → fatty liver.

25. What is the precursor of sphingomyelin?

Ceramide.

26. Which enzyme converts ceramide + phosphocholine → sphingomyelin?

Sphingomyelin synthase.

27. Name the storage disease with sphingomyelin accumulation.

Niemann–Pick disease (sphingomyelinase deficiency).

28. What is the classic sign of Niemann–Pick disease?

Cherry-red spot + hepatosplenomegaly.

29. What lipid accumulates in Gaucher disease?

Glucocerebroside.

30. What enzyme is deficient in Gaucher disease?

β-Glucocerebrosidase.

31. What is the histological hallmark of Gaucher cells?

Macrophages with crumpled tissue-paper cytoplasm.

32. What disease has GM₂ ganglioside accumulation?

Tay–Sachs disease.

33. What is the enzyme deficiency in Tay–Sachs?

Hexosaminidase A.

34. What is unique about Tay–Sachs compared to Niemann–Pick?

Cherry-red spot without hepatosplenomegaly.

35. Which disease has “globoid cells”?

Krabbe disease (galactocerebrosidase deficiency).

36. What accumulates in Metachromatic leukodystrophy?

Sulfatides.

37. What enzyme is deficient in Metachromatic leukodystrophy?

Arylsulfatase A.

38. Which storage disease is X-linked?

Fabry disease.

39. What accumulates in Fabry disease?

Ceramide trihexoside.

40. What enzyme is deficient in Fabry disease?

α-Galactosidase A.

41. What disease involves ceramide accumulation?

Farber disease (ceramidase deficiency).

42. Why are PUFA important for skin health?

They maintain skin barrier and reduce inflammation.

43. Which fatty acid metabolism step is bypassed in MCFA oxidation?

Carnitine shuttle (not required).

44. What enzyme rearranges cis-Δ³ double bond during unsaturated FA oxidation?

Enoyl-CoA isomerase.

45. Why do PUFA yield slightly less ATP?

Because FADH₂-generating steps are skipped due to double bonds.

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MCFA, PUFA, Prostaglandins and Compound Lipids

Topic Overview

⭐ Digestion of Medium-Chain Fatty Acids (MCFAs)

⭐ Characteristics of Medium-Chain Fatty Acids

⭐ Process of Digestion

⭐ 1. In the Stomach

⭐ 2. In the Small Intestine

Medium-chain fatty acids do NOT require:

Why?

⭐ 3. Absorption into Enterocytes

⭐ 4. Transport After Absorption

⭐ Metabolic Fate in Liver

⭐ Clinical Significance

⭐ Monounsaturated Fatty Acids (MUFA)

⭐ Common MUFAs

⭐ Sources

⭐ Structure and Properties

⭐ Functions of MUFAs

⭐ Clinical Importance

⭐ β-Oxidation of Unsaturated Fatty Acids

⭐ Case 1: Oxidation of Monounsaturated Fatty Acids

⭐ Problem

⭐ Solution: Enoyl-CoA Isomerase

⭐ Energy Yield

⭐ Case 2: Oxidation of Polyunsaturated Fatty Acids (PUFA)

⭐ Combined Flow (β-Oxidation of Unsaturated Fatty Acids)

⭐ Clinical Significance

⭐ Polyunsaturated Fatty Acids (PUFA)

⭐ Common PUFAs

Omega-6 (n-6) family

Omega-3 (n-3) family

⭐ Functions of PUFAs

⭐ Health Benefits

Omega-3

Omega-6

⭐ Sources of PUFAs

Omega-6

Omega-3

⭐ Deficiency Features

⭐ Metabolism of PUFAs (Overview)

⭐ Desaturation of Fatty Acids

⭐ Key Features

⭐ Why Some Fatty Acids Are Essential?

⭐ Desaturation Reaction (Simplified)

⭐ Sequence of Desaturation + Elongation

⭐ Clinical Points

⭐ Ultra-Short Revision

⭐ Polyunsaturated Fatty Acids (PUFA)

⭐ Essential PUFAs

⭐ Important PUFA Families

Omega-6 Series

Omega-3 Series

⭐ Functions of PUFAs

⭐ Sources

⭐ Deficiency

⭐ Clinical Notes

⭐ Desaturation of Fatty Acids

⭐ Desaturase Enzymes in Humans

⭐ Why Essential Fatty Acids Are Essential

⭐ Requirements for Desaturation

⭐ Desaturation Reaction (Simplified)

⭐ Example: Making Arachidonic Acid

⭐ Clinical Importance

⭐ High-Yield Summary

⭐ Essential Fatty Acids (EFA)

⭐ The Essential Fatty Acids

1. Linoleic Acid (18:2, ω-6)

2. α-Linolenic Acid (18:3, ω-3)

⭐ Functions of EFAs

⭐ Deficiency Features

⭐ Eicosanoids

⭐ Sources of Eicosanoids

⭐ Pathways

1. Cyclooxygenase (COX) Pathway → Prostaglandins + Thromboxanes

2. Lipoxygenase (LOX) Pathway → Leukotrienes + Lipoxins

⭐ Prostaglandins

⭐ Precursor

⭐ Types & Functions

1. PGE₂ – “Inflammatory Prostaglandin”

2. PGI₂ (Prostacyclin) – “Platelet Protector”