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Chapter 5: Fatty Acid Synthesis - Full Notes Explained

Overview

These are notes from pages 60-61 of a biochemistry lecture book covering de novo fatty acid synthesis - how the body builds fatty acids from scratch, primarily in the liver cytoplasm.

Page 60 - The Citrate Shuttle & Acetyl-CoA Transport

Site & Trigger

Site: Liver cytoplasm (also mammary gland and, to a lesser extent, adipose tissue)
Why after a carbohydrate-rich meal? Excess carbs are converted to fatty acids:

Carbohydrates → Pyruvate → Acetyl-CoA → ↑↑ Fatty acid synthesis → TG → VLDL (blood)

The note "Fatty liver: block exit" refers to when VLDL export is impaired (e.g., alcohol, choline deficiency), causing triglycerides to accumulate in hepatocytes - fatty liver disease.

The Core Problem: Acetyl-CoA Cannot Cross the Mitochondrial Membrane

Fatty acid synthesis needs acetyl-CoA in the cytoplasm, but acetyl-CoA is made in the mitochondria (from pyruvate by pyruvate dehydrogenase). The CoA portion cannot cross the inner mitochondrial membrane - so a workaround is needed.

The Citrate Shuttle - Step by Step

Inside the mitochondria: Acetyl-CoA + Oxaloacetate → Citrate (by citrate synthase). This happens especially when ATP is high (inhibiting isocitrate dehydrogenase in the TCA cycle), so citrate accumulates - a "high energy signal."
Transport: Citrate crosses the inner mitochondrial membrane via the tricarboxylate transporter into the cytoplasm.
In the cytoplasm: The enzyme ATP-citrate lyase (ACL) cleaves citrate:

Citrate + CoA-SH + ATP → Acetyl-CoA + Oxaloacetate + ADP + Pᵢ
Oxaloacetate recycling: Oxaloacetate → Malate (uses NADH) → Pyruvate (via malic enzyme, releases CO₂ and generates NADPH) → re-enters mitochondria.

The NADPH generated here is important - it is used as the reducing agent for fatty acid synthesis.

Summary box from the diagram:

Mitochondrial acetyl-CoA cannot cross directly
It "hitchhikes" out as citrate
ATP-citrate lyase releases it in the cytoplasm
Oxaloacetate is sent back via the malate-pyruvate route
Lippincott's Biochemistry 8th ed, p. 518-520
Basic Medical Biochemistry 6e, p. 1119

Page 61 - Key Enzymatic Steps

New Drug: Bempedoic Acid

The image shows Bempedoic Acid Tablets 180 mg. The handwritten note explains:

Bempedoic acid = Inhibits ATP-citrate lyase → used for treatment of hypercholesterolemia

Since ATP-citrate lyase (ACL) is the enzyme that releases acetyl-CoA in the cytoplasm for cholesterol and fatty acid synthesis, blocking it reduces cholesterol production. It is a prodrug - activated only in the liver (not in muscle, which avoids the myopathy side effects of statins). It is used as an add-on or alternative to statins.

Rate-Limiting Step: Acetyl-CoA Carboxylase (ACC)

Next step: Acetyl-CoA (2C) is converted to Malonyl-CoA (3C) by ACC, the rate-limiting enzyme:

A-CoA (2C) + CO₂ →[ACC]→ Malonyl-CoA (3C)

Remember "ABC" for ACC requirements:

Letter	Requirement
A	ATP (energy for the reaction)
B	Biotin (cofactor, covalently bound - carries the CO₂)
C	Citrate (allosteric activator)

ACC Regulation (critical for exams):

Activated by: Citrate (allosteric - causes ACC protomers to polymerize into active form)
Inhibited by: Palmitoyl-CoA (end product feedback inhibition - causes depolymerization); AMPK phosphorylation (activated by glucagon/epinephrine via cAMP-PKA cascade)
Insulin → dephosphorylates ACC → activates it (promotes fat synthesis in fed state)
Metformin → activates AMPK → phosphorylates/inactivates ACC → reduces fatty acid synthesis
Lippincott's Biochemistry 8th ed, p. 520-522

FA Synthase Complex - Final Product

The Fatty Acid Synthase (FAS) complex is a multifunctional enzyme that assembles the fatty acid:

Inputs: 1 Acetyl-CoA (starter unit) + 7 Malonyl-CoA (each adds 2 carbons after CO₂ is lost)
Output: Palmitic acid (16C, saturated) - a 16-carbon fully saturated fatty acid (16:0)
PYQ (Previous Year Question) answer: The fatty acid made in human liver = Palmitic acid (16C, saturated)

Each cycle: Malonyl-CoA donates 2 carbons (decarboxylation releases 1 CO₂), and NADPH provides reducing equivalents.

7 × Malonyl-CoA + 1 × Acetyl-CoA + 14 NADPH → Palmitate + 7 CO₂ + 14 NADP⁺ + 8 CoA + 6 H₂O

Palmitate can be further elongated (in smooth ER) or desaturated to form other fatty acids.

Q1 Answer Explained

Q: Which enzyme is the primary rate-limiting step in de novo fatty acid synthesis, and which allosteric modifier activates it?

✅ Correct answer: C - Acetyl-CoA carboxylase (ACC); Activated by Citrate

Why each option is wrong/right:

A. Fatty acid synthase; Palmitoyl-CoA - FAS is NOT rate-limiting; Palmitoyl-CoA actually inhibits ACC (feedback inhibition)
B. Acyl-CoA synthetase; Malonyl-CoA - This enzyme activates fatty acids for beta-oxidation, not synthesis
C. ACC; Citrate ✅ - ACC is THE rate-limiting step; citrate is the allosteric activator (logical because citrate's presence signals excess acetyl-CoA is available)
D. CPT-1; Insulin - CPT-1 is the rate-limiting step for beta-oxidation (fatty acid breakdown), not synthesis; it is inhibited by malonyl-CoA

Key Connections to Remember

Concept	Detail
Site of FA synthesis	Liver cytoplasm
Acetyl-CoA shuttle molecule	Citrate
Shuttle enzyme (cytoplasm)	ATP-citrate lyase
New drug targeting ACL	Bempedoic acid (for hypercholesterolemia)
Rate-limiting enzyme	Acetyl-CoA carboxylase (ACC)
ACC cofactor	Biotin (Vitamin B7)
ACC activator	Citrate
ACC inhibitor	Palmitoyl-CoA, AMPK (via glucagon/epinephrine)
Final product of FAS	Palmitic acid (16:0, 16C saturated)
NADPH source	Malic enzyme (OAA → Pyruvate), Pentose phosphate pathway

Explain CPT-1 regulation and why it's inhibited by malonyl-CoA

CPT-1 (Carnitine Palmitoyltransferase-1) is the rate-limiting enzyme for fatty acid beta-oxidation. It sits on the outer mitochondrial membrane and transfers long-chain fatty acyl groups from CoA to carnitine, allowing them to enter the mitochondria for oxidation. Its inhibition by malonyl-CoA is one of the most elegant examples of metabolic reciprocal regulation - when you're building fats, you simultaneously shut down fat burning.

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Public Health Practical Class 2 - Epidemiology as the Foundation of Public Health

The document covers 7 sections:

Introduction to Epidemiology - definition, key concepts (population at risk, case definition, exposure, outcome, risk factor, causation, surveillance)
Incidence vs Prevalence - formulas, difference, clinical examples (TB = incidence; diabetes registry = prevalence)
Measures of Risk - Absolute Risk, Attributable Risk, Relative Risk (RR) with formulas and interpretation (RR=1 no association, >1 risk factor, <1 protective)
Odds Ratio (OR) - 2×2 table, formula (ad/bc), used in case-control studies
Types of Epidemiological Studies - Descriptive, Cross-sectional, Case-Control, Cohort, RCT (gold standard)
Causation in Epidemiology - Bradford Hill Criteria, classic smoking → lung cancer example
Outbreak Investigation Case - food poisoning in a dormitory scenario for class discussion

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