Lipids and Fatty acid metabolism😊😍

Applied Biochemistry

Essential FA Deficiency

• Acanthosis

• Follicular hyperkeratosis / Phrynoderma

• Fatty liver

• Mitochondrial membrane damage

↑ Trans FA Effects

• ↓ Membrane fluidity

• ↑ Insulin resistance

• ↑ Dyslipidemia

• ↑ Inflammation

Omega-3 FA Benefits

• ↓ TG & CV risk

• ↓ Platelet aggregation

• ↓ Inflammation

• ↓ Mental & neurodegenerative disease

• Supports infant brain development

• Useful in: Type 2 DM, ADHD, NAFLD

ㅤ	SFA	MUFA	PUFA	PUFA
ㅤ	ㅤ	Omega -9	Omega -3	Omega -6
Example	• Lauric acid  • Stearic acid  • Palmitic acid	Oleic acid	α-linolenic acid Most essential fatty acid	Linoleic acid
Richest sources	Animal sources One plant source: Coconut oil	• Mustard oil • Groundnut • Olive • Avocado	Flax seed oil One animal source: Fish	Safflowers
Long/complex chain derivative & richest source	-	-	• Eicosapentaenoic acid • α-linolenic acid • Timnodonic acid • Cervonic acid ↳ Breast milk ↳ Fish ↳ Algal oil	• Linoleic acid • γ-linolenic acid • Arachidonic acid : ↳ Milk, egg Derivatives: ↳ Eicosanoids (Prostaglandins, Leukotrienes, Thromboxane A2)
ㅤ	Saturated Laura (Lauric acid) stearingil (stearic acid) coconut (coconut oil) palmil (Palmitic oil) kond idich	MUFA → 9 () Ola (Oleic) ayi MUST () goto GOA ()	3 → F → Flax → Fish	6 → FF → saFFlower

Phrynoderma / follicular hyperkeratosis/ Toad Skin

Without 13-cis retinoic acid:

• Earliest skin manifestation: Dryness

• Caused by Vitamin A or essential fatty acid deficiency.

• Small papillary lesions
• Dry, rough, hyperkeratotic papules
• Small keratin plug is at the tip.
• Near back of elbows, knees, joint areas

• Pathology: Impaired follicular keratinisation (Vit A essential)

Composition of breast milk Vs Cow milk

Component	Breast Milk	Cow Milk
Lactose	• 2x buffalo milk • 7 g/dl Advantages • More energy as carbohydrate • Helps in formation of galactose & Lactobacillus in intestine	- 4.5 g/dl
Proteins	• 25% of buffalo milk. • 1 g/dl Advantages • Best quality protein • Higher in Soluble proteins • Lesser solute load on kidneys • Richer in whey proteins like Lactoglobulin (easily digestible) • Richer in Cysteine, Methionine (needed for CNS development)	- 3.5 g/dl
Lipids	• 50% of buffalo milk. • Richer in PUFA (polyunsaturated fatty acids) PUFA in Human Milk Major types: • Linoleic acid → precursor of arachidonic acid. • α Linolenic acid → precursor of docosahexaenoic acid (DHA). DHA (Docosahexaenoic acid) / Cervonic acid ↳ Important for CNS development (Promotes myelination)	ㅤ
Energy	• 50% of buffalo milk.	ㅤ
Minerals	• Ca : Phosphate = 2:1 → favours calcium absorption • Iron is more easily absorbable than in cow's milk	Richer in phosphate → hinders calcium absorption → ↑ risk of hypocalcemia
Vitamins	Contains all vitamins except: • Vitamin D, K, B12 • (especially in strictly vegan mothers)	ㅤ

• Casein : Albumin ratio = 1:1

• Vitamin C:
• maximum of all milk sources (↑ Iron absorption).

Breast Milk deficient

• Vitamin D (400 IU/day)
• Recommended to all babies till 1 year

• Vitamin K –
• Given to all babies
• 1 mg IM at birth
• Prevents hemorrhagic disease of the newborn

• Iron ???
• Adequate (↑ Bioavailability).

Babies predominantly cow milk fed:

• ↑ Risk of hypocalcemia, tetany, seizures

• ↑ Risk of scurvy
• Due to Vitamin C deficiency in cow's milk
• Vitamin C is heat labile (gets destroyed when cow's milk is boiled)

Breast milk contains Anti-infective substances

• Mnemonic - Teach for PLAB

• Transforming growth factor β

• Phagocytic macrophages

• Lactoferrin

• Lysozyme

• Antibodies especially IgA

• Bifidus factor

• Bile stimulated lipase

Amphipathic vs Non-Amphipathic Lipids

• Amphipathic molecules have both:
• Hydrophilic (polar) region
• Hydrophobic (nonpolar) region

Lipid Types & Amphipathicity

Related Concepts

• Fructose → ↑ Acetyl CoA → FA synthesis → TAG → Dyslipidemia

• NADPH → used in Cholesterol & Steroid Synthesis

• Malonyl CoA → ⛔ β-Oxidation (CPT-1)

Fatty Acid Synthesis

• Active Tissues:
• Liver,
• Adipose,
• Lactating mammary gland,
• Adrenal cortex,
• Thyroid, Testis, RBCs

• Low Activity:
• Skeletal muscle,
• Non-lactating mammary

• Organelle:
• Cytoplasm,
• SER (cholesterol synthesis)

• M/C product
• Palmitic acid

Substrate & Transport

• Starting Molecule:
• Acetyl CoA

Reaction	Via	Location
Acetyl-CoA + OAA → Citrate	Citrate synthase	Mitochondria
↓	TCA transporter / Citrate shuttle	Mitochondrial membrane
Citrate → Acetyl-CoA + OAA	ATP Citrate Lyase	Cytosol

• Transport:
• Citrate Shuttle / Tricarboxylate transporter

• Mnemonic:
• Car burns (Carnitine → β oxidation) fuel
• sit & synthesize (citrate → FA synthesis)

Steps in cytosol

1. Acetyl CoA → Malonyl CoA
• via Acetyl CoA Carboxylase
• Require B7 (ABC)
• RLE

REVISE BIOTIN

Biotin (B7) Coenzyme for	Reaction	Name
Pyruvate carboxylase	Pyruvate → Oxaloacetate	• Gluconeogenesis
Acetyl CoA carboxylase	Acetyl CoA → Malonyl CoA	• Fatty acid synthesis
Propionyl CoA carboxylase	Propionyl CoA → Methyl Malonyl CoA	• Fatty acid oxidation • Branched-chain AA breakdown

• Mnemonic for biotin:
• ABC PAPify
• ABC - ATP, BIOTIN, CO2 FOR CARBOXYLATION
• When depressed (depression) due to alopecia (), dermatitis () and rash → exercise cause fatigue and eat egg (avidin in egg white inhibits B7)
• Bought a cat → Tom cat → Peed everywhere → Tom cat urine odour () in multiple carboxylase enzyme deficiency ()

2. Fatty Acid Synthase (FAS) complex
• Homodimer
• Each monomer: 3 subunits
1. Condensing unit
2. Reduction unit
• NADPH is required for steroid and cholesterol synthesis
3. Releasing unit
• Thioesterase
• Acyl carrier protein
• Contains pantothenic acid (B5)

Cholesterol Synthesis

Steps

1. 2 × Acetyl CoA

2. Acetoacetyl CoA + Acetyl CoA → HMG CoA
• via HMG CoA synthase

3. HMG CoA → Mevalonate
• via HMG CoA reductase
• RLE

4. Mevalonate → 2 × Isopentenyl (5C) → Geranyl (10C)

5. → 2 × Farnesyl (15C) → Squalene (30C) → Cholesterol (27C)

Applied

• Statins ⟶ ⛔ HMG CoA reductase → ↓ Coenzyme Q (Derived from Farnesyl) → Myopathy

Triglyceride Formation

• DHAP (from glycolysis) → Glycerol-3-P

• Glycerol-3-P + Fatty Acyl-CoA → TAG

• Stored in Adipose Tissue

Bile Acid Synthesis

Steps

1. Cholesterol + Vit C → 7 OH cholesterol
• via 7 α hydroxylase (RLE)

Points

• Conjugation: By Taurine + Glycine

• Lithocholic acid → undergoes least enterohepatic circulation

Beta-Oxidation of Fatty Acids

NOTE

Steps:

1. Activation of Fatty Acids:

• Location: Cytoplasm.

• Fatty acid → Acyl-CoA
• Acyl-CoA synthetase (thiokinase) or fatty acyl-CoA synthetase.
• Cost: 2ATP

2. Carnitine Transport:

• Transports long-chain fatty acyl-CoA into the mitochondria

• Fatty acid less than 14C → Not required

↳ Carnitine palmitoyltransferase I (CPT-I/CAT-1)

• Long-chain fatty acyl-CoA → Fatty acyl-carnitine

• RLE

• Gateway of beta-oxidation

• ⛔ by malonyl-CoA
• Mnemonic → CAT (CAT 1) nu BETA (β oxidation) MALA (Malonyl CoA) ittu kodukkum

↳ Carnitine-acylcarnitine translocase

• Shuttles Fatty acyl-carnitine across IMM

↳ Carnitine palmitoyltransferase II (CPT-II/CAT-2)

• Fatty acyl-carnitine → Long-chain Fatty acyl-CoA

3. Beta-Oxidation Cycle

• Location: Mitochondrial matrix.

• Long chain acyl CoA undergoes → sequential removal of Acetyl CoA

• Each cycle produces 1 acetyl-CoA, 1 NADH, and 1 FADH₂.

• Total ATP per cycle: 1.5 ATP (FADH₂) + 2.5 ATP (NADH) = 4 ATP.

• Acetyl-CoA produced enters the TCA cycle.

Energy Yield:

Even chain FA

• Palmitic acid (C16)
• Cycles: 7.
• Acetyl-CoA: 8.
• ATP from cycles: 7 × 4 = 28 ATP.
• ATP from acetyl-CoA: 8 × 10 = 80 ATP.
• Activation: 2 ATP.
• Net ATP: 80 + 28 - 2 = 106 ATP.

Odd chain FA:

• Eg. 17 C fatty acid:
• consider as 16C + 1 Propionyl CoA
• ATP from 1 Propionyl CoA = 5 ATP
• Propionyl-CoA → succinyl-CoA
• Propionyl-CoA carboxylase (biotin-dependent).
• Methylmalonyl-CoA racemase.
• Methylmalonyl-CoA mutase (vitamin B12-dependent).
• Cycles: 7.
• But, Acetyl-CoA: 7
• Generates
• 1 Propionyl-CoA +
• 7 Acetyl-CoA
• 7 cycle of beta-oxidation
• – 2 ATP for FA activation
• 5 ATP + 70 ATP + 28 ATP – 2 ATP = 101 ATP
• Odd-chain fatty acids → yield 1 propionyl-CoA

Variations in Beta-Oxidation:

Applied Biochemistry / Disorders:

Carnitine Deficiency (Systemic Primary)

• Defect:
• No cellular uptake of carnitine → toxic accumulation of LCFAs in cytosol.

• Features:
• Muscle weakness
• Hypotonia
• Hypoketotic hypoglycemia
• Dilated cardiomyopathy

• Carn thinnan pattunilla → have muscle weakness (hypotonia) and big heart (DCM)

MCAD Deficiency (Medium Chain Acyl-CoA Dehydrogenase)

• Management:
• Avoid fasting

• Mechanism:
• ↓ FA breakdown
• accumulation of fatty acyl carnitines & dicarboxylic acids
• via ω-oxidation
• ↓ Acetyl-CoA → no ketone bodies (Rothera’s test –ve)
• ↓ ATP → fasting hypoglycemia.

• Clinical:
• Vomiting, lethargy, seizures, coma
• Liver dysfunction, hyperammonemia
• SIDS (cradle death) in infants
• MCAD → Liver gone in infants

Jamaican Vomiting Sickness

• Cause:
• Consumption of unripe Ackee fruit (contains hypoglycin).

• Mechanism:
• ↓ β-oxidation → ↓ Acyl-CoA intermediates → ↓ Acetyl-CoA.
• ↓ Ketone body formation (Rothera’s test –ve).

• Result:
• Fasting hypoglycemia.

Refsum’s Disease

• Defect: Phytanoyl-CoA oxidase (hydroxylase) deficiency.

• Pathogenesis:
• ↓ α-oxidation of branched chain FA (phytanic acid)
• In peroxisomes
• Mnemonic: Refsum → Referee for Fight (Phytanic acid) → RIP
• accumulation of phytanic acid.

• Mnemonic: RIPC
• Retinitis pigmentosa
• Ichthyosis (scaly skin)
• Peripheral neuropathy
• Cardiac arrhythmias

• Course:
• Asymptomatic > symptomatic (worsens with curd/milk).

• Management:
• Restrict dairy & green vegetables.
• Curd, Milk, Goat Meat

Adrenoleukodystrophy

Zellweger Syndrome

• Cerebrohepatorenal Disease

• Defect:
• Peroxisome targeting sequence (PTS) mutation.
• PEX gene mutation ?
• PEX codes for peroxins 
• (Proteins for peroxisome synthesis)

• Inheritance: AR

• Pathology:
• Peroxisomes lack enzymes ("peroxisomal ghost").
• Accumulation of VLCFA & phytanic acid
• ↓ plasmalogens
• Neurological damage.

• Mnemonic:
• Zettle (Zellweger) Down (resemble downs) with brush (Brushfield spots in eye) → Ghost (Ghost peroxisomes)

• Clinical features (resembles Down’s syndrome):
• Mongoloid facies
• Hypertelorism
• Unslanting palpebral fissure
• Frontal bossing, high forehead
• Brushfield spots
• Intellectual disability

Ketone Bodies

• Products of incomplete fatty acid oxidation.

• Complete oxidation:
• n-carbon fatty acid yields n/2 Acetyl CoA.
• Acetyl CoA enters Citric acid cycle, exhaled as CO₂.

• Incomplete oxidation:
• Acetyl CoA does not enter Citric acid cycle.
• Molecules condense to form ketone bodies.

---

• Three ketone bodies:

Ketone Bodies	Features
Acetone	• Volatile → fruity odour in breath
Acetoacetate	• Primary ketone body • Detected in Urine tests
β-Hydroxybutyrate	• M/c KB utilized (Predominant) • Secondary Ketone Body • Most acidic

---

Ketone body utilisation KLP

---

Can’t use ketone bodies:

Cells	D/t absence of
RBCs	Mitochondria
Liver cells	Thiophorase

Don't Confuse “thio” enzymes

Enzyme	Reaction	Relevance
Thiophorase / Succinyl CoA - Acetoaceyl CoA transferase/ β-ketoacyl-CoA transferase	Acetoacetate → Acetoacetyl CoA	• Absent in Liver • Cannot utilize Ketone body
Thiolase	Acetoacetyl CoA → 2 acetyl CoA	• Last steps of β oxidation
Thiokinase	Acyl CoA → Trans enoyl CoA	• Initial steps of β oxidation

Don't Confuse

---

Fate of Acetyl CoA	Enzyme	Note
↳ Fatty acid synthesis	Acetyl CoA Carboxylase	• Stored as Triacylglycerol
↳ Cholesterol synthesis	HMG-CoA reductase	• In fed state • Stored as Cholesterol ester • RLE in cholesterol synthesis • ⛔ by statins
↳ KB Synthesis	HMG-CoA lyase	• In Starvation

• NOTE:
• HMG-CoA synthase
• Common in both cholesterol and KB synthesis
• RLE in ketone body synthesis

Applied Aspect