Lipid Metabolism — Fatty Acid Oxidation, Synthesis, Ketogenesis, and Cholesterol

🟢 Lite — Quick Review (1h–1d)

Rapid summary for last-minute revision before your exam.

Lipid Metabolism covers how fatty acids are broken down for energy (β-oxidation), built up (fatty acid synthesis), turned into ketone bodies (ketogenesis), and how cholesterol and lipoproteins function. INI CET frequently tests β-oxidation steps and ATP yield, ketone body functions, lipoprotein functions, and fatty acid synthesis.

High-Yield Facts for INI CET:

• β-oxidation location: Mitochondrial matrix; fatty acid enters as CoA ester via carnitine shuttle (CPT-I on outer membrane, CPT-II on inner membrane)
• β-oxidation yields: Per round: 1 NADH (2.5 ATP) + 1 FADH₂ (1.5 ATP) + 1 acetyl-CoA (12.5 ATP) = ~5 ATP per 2-carbon unit
• β-oxidation of palmitate (C16): 8 rounds → 8 acetyl-CoA + 7 NADH + 7 FADH₂ → ~106 ATP total
• Ketone bodies: Produced in liver mitochondria from acetyl-CoA; acetoacetate and β-hydroxybutyrate; used by brain, heart, and skeletal muscle during prolonged fasting
• Cholesterol synthesis: HMG-CoA reductase is the rate-limiting enzyme (statin target)

⚡ Exam tip: Medium-chain fatty acids (C6-C12) can enter mitochondria without carnitine (diffuse directly), making them useful in MCAD deficiency. Very long-chain fatty acids (>C22) require peroxisomal β-oxidation first.

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🟡 Standard — Regular Study (2d–2mo)

Standard content for students with a few days to months.

Lipid Metabolism — INI CET (AIIMS PG) Study Guide

Fatty Acid Structure and Naming

Fatty Acid Basics:

• Composed of hydrocarbon chain with terminal carboxyl group (-COOH)
• Even number of carbons (C2 to C28 or more)
• Saturated: No double bonds (straight chain, pack tightly → solid at room temperature)
• Unsaturated: One or more double bonds (kinks prevent tight packing → liquid at room temperature)
• Double bond geometry: cis (natural, causes kink) vs trans (unnatural, associated with partially hydrogenated oils)

Fatty Acid Naming:

• Systematic: Number of carbons × number of double bonds (C:n)
• Palmitic acid = C16:0 (16 carbons, no double bonds)
• Stearic acid = C18:0
• Oleic acid = C18:1 (cis-9, one double bond at C9)
• Linoleic acid = C18:2 (cis-9,12 — essential fatty acid, cannot be synthesized by humans)
• α-Linolenic acid = C18:3 (cis-9,12,15 — essential fatty acid)

Essential Fatty Acids:

• Linoleic acid (ω-6) and α-linolenic acid (ω-3) → cannot be synthesized de novo
• Must be obtained from diet
• Functions: Membrane phospholipids, eicosanoid precursors (prostaglandins, leukotrienes, thromboxanes)

Fatty Acid Activation and Transport into Mitochondria

Activation (in cytosol):

• Fatty acid + CoA + ATP → Fatty acyl-CoA + AMP + PPi (catalyzed by acyl-CoA synthetase/fatty acid thiokinase)
• PPi → 2 Pi (inorganic pyrophosphatase) → irreversible, drives the reaction forward
• Acyl-CoA synthetase requires Mg²⁺ and is found in the cytosol

Carnitine Shuttle (the rate-limiting step for β-oxidation):

1. Carnitine palmitoyltransferase I (CPT-I): Outer mitochondrial membrane; converts fatty acyl-CoA → fatty acyl-carnitine (releases CoA)
2. Carnitine-acylcarnitine translocase: Transports fatty acyl-carnitine into matrix (1-for-1 exchange with carnitine exiting)
3. Carnitine palmitoyltransferase II (CPT-II): Inner mitochondrial membrane; converts fatty acyl-carnitine → fatty acyl-CoA + carnitine (CoA is regenerated in matrix)

Regulation of CPT-I:

• Malonyl-CoA (intermediate in fatty acid synthesis) inhibits CPT-I → when fatty acid synthesis is active, β-oxidation is blocked
• This prevents futile cycling (simultaneous synthesis and breakdown of fatty acids)
• AMPK phosphorylates and inhibits malonyl-CoA decarboxylase → decreases malonyl-CoA → activates β-oxidation during exercise

β-Oxidation (Fatty Acid Oxidation)

Steps in each round (repeats until all carbons are acetyl-CoA):

Step 1: Acyl-CoA Dehydrogenase:

• Removes 2 H atoms from α (C2) and β (C3) carbons of fatty acyl-CoA
• Creates a trans double bond between α and β carbons
• Produces FADH₂ (tightly bound to enzyme as prosthetic group)
• Produces: trans-Δ²-enoyl-CoA

Step 2: Enoyl-CoA Hydratase:

• Adds H₂O across the trans double bond
• Produces: L-3-hydroxyacyl-CoA (L-β-hydroxyacyl-CoA)

Step 3: β-Hydroxyacyl-CoA Dehydrogenase:

• Oxidizes the β-hydroxy group to a keto group
• Uses NAD⁺ as electron acceptor → produces NADH
• Produces: β-ketoacyl-CoA

Step 4: β-Ketoacyl-CoA Thiolase (Thiolase):

• Cleaves between α and β carbons
• Adds CoA (from free CoA pool) to the acetyl group → acetyl-CoA
• Leaves behind a fatty acyl-CoA that is 2 carbons shorter
• This is the cleavage step

ATP Yield from β-Oxidation of Palmitate (C16):

• 8 rounds of β-oxidation = 8 acetyl-CoA
• 7 NADH × 2.5 = 17.5 ATP
• 7 FADH₂ × 1.5 = 10.5 ATP
• 8 acetyl-CoA × 12.5 ATP = 100 ATP
• Total: ~106 ATP per palmitate (less 2 ATP for activation cost = ~104 ATP net)

Odd-chain fatty acids: Yield one propionyl-CoA (3 carbons) → converted to succinyl-CoA → enters TCA cycle (glucogenic)

Ketogenesis

Location: Hepatocyte mitochondria (liver is the ONLY organ that makes ketone bodies) Purpose: Convert excess acetyl-CoA (from fatty acid β-oxidation during fasting) into water-soluble fuel molecules for brain, heart, and skeletal muscle

The Three Ketone Bodies:

1. Acetoacetate (AcAc): Produced first; can be reduced to β-hydroxybutyrate or spontaneously decarboxylate to acetone
2. β-Hydroxybutyrate (βHB): Most abundant ketone body (75-80%); produced by mitochondrial β-hydroxybutyrate dehydrogenase (uses NADH)
3. Acetone: Lowest energy; produced by spontaneous decarboxylation of acetoacetate; exhaled through lungs (characteristic “fruity” odor in diabetic ketoacidosis)

Ketogenesis Pathway:

1. HMG-CoA synthase: 2 acetyl-CoA → acetoacetyl-CoA (thiolase); then + 1 acetyl-CoA → HMG-CoA (rate-limiting step)
2. HMG-CoA lyase: HMG-CoA → acetoacetate + CoA (produces acetoacetate)
3. β-hydroxybutyrate dehydrogenase: Acetoacetate + NADH ↔ β-hydroxybutyrate + NAD⁺

Ketone Body Utilization (peripheral tissues):

• Succinyl-CoA:acetoacetate CoA transferase (SCOT): Activates acetoacetate in extrahepatic tissues (liver lacks this enzyme → cannot use its own ketone bodies)
• β-hydroxybutyrate → acetoacetate (by β-hydroxybutyrate dehydrogenase) → acetoacetyl-CoA → acetyl-CoA → TCA cycle

Ketone Body Yield:

• Acetoacetate yields 2 acetyl-CoA = 25 ATP (net ~20 ATP accounting for transport)
• Brain cannot use fatty acids; in prolonged fasting, brain adapts to use ketone bodies for up to 60% of energy needs

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🔴 Extended — Deep Study (3mo+)

Comprehensive coverage for students on a longer study timeline.

Fatty Acid Synthesis (De Novo Lipogenesis)

Location: Cytosol (liver and adipose tissue) Building block: Acetyl-CoA (from glucose via glycolysis → citrate → exported from mitochondria) Reducing power: NADPH (from HMP shunt via malic enzyme and isocitrate dehydrogenase)

Key enzyme: Acetyl-CoA Carboxylase (ACC):

• Biotin-containing enzyme; carboxylates acetyl-CoA → malonyl-CoA
• ACC is the rate-limiting enzyme of fatty acid synthesis
• Insulin activates ACC (dephosphorylation); glucagon/epinephrine inhibits (phosphorylation by PKA)
• Citrate activates ACC; acyl-CoA (high energy) inhibits (feedback)
• Malonyl-CoA also inhibits CPT-I → blocks fatty acid entry into mitochondria

Fatty Acid Synthase (FAS):

• Large, multifunctional enzyme complex (single polypeptide in mammals, dimeric)
• Contains: acyl carrier protein (ACP), β-ketoacyl synthase (KS), β-hydroxyacyl reductase, enoyl reductase, thioesterase
• Elongates by adding 2-carbon units (malonyl-CoA) in a cyclic manner
• Final product: Palmitate (C16:0) — the only fatty acid that can be synthesized de novo
• For longer chains (C18 and beyond): Elongases in ER (malonyl-CoA dependent) add 2 carbons at a time

Steps of Fatty Acid Synthesis:

1. Acetyl-CoA loaded onto KS (condensing enzyme)
2. Malonyl-CoA loaded onto ACP
3. Condensation: Acetyl group transferred to malonyl → acetoacetyl-ACP (releases CO₂)
4. Reduction: Acetoacetyl → β-hydroxybutyryl-ACP (NADPH → NADP⁺)
5. Dehydration: β-hydroxybutyryl → crotonyl-ACP (trans-Δ²)
6. Reduction: Crotonyl → butyryl-ACP (NADPH → NADP⁺)
7. Butyryl (4C) loaded onto KS → condensation with malonyl-CoA → repeat

Cholesterol Metabolism

Cholesterol Structure:

• Steroid nucleus: Four fused carbon rings (cyclopentanoperhydrophenanthrene)
• Hydrocarbon tail, single hydroxyl group
• Synthesized from acetyl-CoA; rate-limiting enzyme is HMG-CoA reductase
• Present in all animal cell membranes; precursor for steroid hormones, bile acids, vitamin D

Cholesterol Synthesis Steps:

1. HMG-CoA reductase: HMG-CoA → mevalonate (rate-limiting step; statin target)
2. Mevalonate → isopentenyl pyrophosphate (IPP) → dimethylallyl pyrophosphate (DPP)
3. Condensation of IPP + DPP → geranyl pyrophosphate → farnesyl pyrophosphate → squalene → lanosterol → cholesterol (via ~19 steps)

Cholesterol Transport and Lipoproteins:

Lipoprotein	Source	Function
Chylomicrons	Intestine	Transport dietary TG and cholesterol from gut to tissues
VLDL	Liver	Transport endogenous TG to peripheral tissues
IDL	VLDL remnants	Intermediate between VLDL and LDL
LDL	VLDL (modified)	Transport cholesterol to peripheral tissues (bears atherogenic risk)
HDL	Liver, intestine	Reverse cholesterol transport (returns cholesterol to liver); anti-atherogenic

LDL receptor: Takes up LDL from blood (binds apoB100); defective in familial hypercholesterolemia → very high LDL cholesterol

Statins: Inhibit HMG-CoA reductase → reduce cholesterol synthesis → upregulate LDL receptors → increased LDL clearance from blood

Cholesterol esters: Cholesterol + fatty acid (acyl-CoA:cholesterol acyltransferase/ACAT); stored in lipid droplets

Lipoprotein Metabolism and Disorders

Hyperlipidemias:

Type	Elevated Lipids	Risk
I	Chylomicrons (TG)	Pancreatitis, xanthomas
IIa	LDL (cholesterol)	Atherosclerosis, CHD
IIb	LDL + VLDL (cholesterol + TG)	Atherosclerosis, CHD
III	IDL (remnants)	Atherosclerosis, CHD
IV	VLDL (TG)	Atherosclerosis, pancreatitis
V	Chylomicrons + VLDL (TG)	Pancreatitis

NCEP Adult Treatment Panel III classification:

• Desirable: Total cholesterol <200, LDL <100, HDL >40, TG <150

Fatty Liver (Hepatic Steatosis):

• Accumulation of TG in hepatocytes (>5% of liver weight)
• Causes: Alcohol (↑ NADH → ↑ fatty acid synthesis, ↓ oxidation), obesity, insulin resistance, diabetes, total parenteral nutrition
• Mechanism: Increased fatty acid delivery to liver + increased hepatic synthesis + decreased export (VLDL) + decreased oxidation
• Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease

Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency:

• Most common fatty acid oxidation disorder
• Cannot perform β-oxidation for C6-C12 fatty acids (these don’t require carnitine)
• Presents in childhood with hypoglycemic crisis during fasting or illness
• TX: Avoid fasting; provide glucose; carnitine supplementation

⚡ INI CET High-Yield: The carnitine shuttle is the rate-limiting step for β-oxidation — CPT-I is inhibited by malonyl-CoA (product of fatty acid synthesis). This prevents futile cycling. HMG-CoA reductase (cholesterol synthesis) is the target of statins. Ketone bodies are made in liver but used in peripheral tissues (liver lacks SCOT enzyme). LDL cholesterol is the primary atherogenic lipoprotein — elevated LDL is the main target for cholesterol-lowering therapy.

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