OIA1003 LIPIDS 3 METABOLISM

Fatty acid oxidation (β-oxidation)

Breakdown of long-chain fatty acids into acetyl-CoA, FADH₂, and NADH — energy-yielding process in mitochondria.

Major energy source

Fatty acid oxidation supplies ~80% of heart/liver energy and is crucial during fasting/hibernation.

Why fats are efficient fuel

More reduced than carbohydrates (higher energy per gram) and stored anhydrously.

Fatty acid activation

Conversion to fatty acyl-CoA by acyl-CoA synthetase (thiokinase) in an ATP-dependent process.

Transport into mitochondria

Fatty acyl-CoA (>12C) converted to acyl-carnitine via CPT-I, transported across inner membrane, reconverted by CPT-II.

Rate-limiting transport enzyme

Carnitine Palmitoyl Transferase I (CPT-I) — inhibited by malonyl-CoA.

β-oxidation process steps

Oxidation (FADH₂), hydration, oxidation (NADH), thiolysis → produces acetyl-CoA.

1 cycle of β-oxidation produces

1 FADH₂, 1 NADH, and 1 acetyl-CoA.

Complete oxidation of palmitate

Produces 8 acetyl-CoA, 7 NADH, and 7 FADH₂ → generates ~106 ATP total.

Regulation of β-oxidation

Inhibited by malonyl-CoA; activated by AMP-activated kinase (AMPK).

AMPK activation

Triggered by low ATP/high AMP → inactivates acetyl-CoA carboxylase → ↓ malonyl-CoA → relieves CPT-I inhibition.

Result of AMPK activation

Promotes fatty acid oxidation and ATP generation.

Lipogenesis definition

Synthesis of fatty acids (mainly palmitate) and TAG from excess glucose/protein in fed state.

Site of fatty acid Synthesis (lipogenesis)

Cytosol of liver and adipose cells.

Source of cytosolic acetyl-CoA

Citrate exported from mitochondria → cleaved by ATP citrate lyase.

Step 1 – Carboxylation (lipogenesis)

Acetyl-CoA + CO₂ → malonyl-CoA by acetyl-CoA carboxylase (biotin-dependent, rate-limiting).

Step 2 – Elongation (lipogenesis)

Fatty acid synthase (FASN) elongates chain via condensation, reduction, dehydration, and reduction.

Main product of FA synthesis (lipogenesis)

Palmitic acid (C16:0).

Reducing agent required

NADPH from pentose phosphate pathway and malic enzyme.

Termination step

Thioesterase cleaves and releases palmitate from FASN complex.

Short-term regulation of ACC

Activated by citrate (allosteric), inhibited by long-chain fatty acyl-CoA.

Phosphorylation control of ACC

AMPK and glucagon/adrenaline → phosphorylate (inactive); insulin → dephosphorylates (active).

Insulin’s role

Promotes glucose uptake → ↑ pyruvate → ↑ acetyl-CoA and glycerol-3-P → ↑ lipogenesis.

Glucagon & adrenaline

↑ cAMP → activates PKA → phosphorylates/inhibits ACC → ↓ lipogenesis.

TAG biosynthesis

3 fatty acyl-CoA esterified to glycerol-3-phosphate → forms TAGs for storage.

Glycerol-3-phosphate sources

From DHAP (via glycerol phosphate dehydrogenase) or free glycerol (via glycerol kinase in liver only).

Key enzymes in TAG synthesis

Glycerol phosphate acyltransferase, phosphatidate phosphatase, diacylglycerol acyltransferase.

TAG storage site

Stored in adipocytes as energy reservoir.

Lipolysis definition

Breakdown of stored TAGs into free fatty acids and glycerol during fasting.

Rate-limiting enzyme (lipolysis)

Hormone-sensitive lipase (HSL) — activated by PKA, inhibited by insulin.

Hormonal control of lipolysis

Epinephrine/glucagon → ↑ cAMP → activates PKA → phosphorylates HSL → TAG breakdown.

Insulin’s effect

↓ cAMP → dephosphorylates/inactivates HSL → lipolysis inhibited.

Glycerol fate (lipolysis)

Transported to liver → converted to glycerol-3-P for TAG synthesis or enters gluconeogenesis.

Fatty acids fate (lipolysis)

Bind albumin → transported to tissues → converted to fatty acyl-CoA → β-oxidation.

Ketone bodies definition

Water-soluble molecules (acetoacetate, β-hydroxybutyrate, acetone) formed from excess acetyl-CoA.

(KB) produced during

Starvation, prolonged fasting, uncontrolled diabetes — when acetyl-CoA > TCA cycle capacity.

Site of production (KB)

Mitochondria of liver hepatocytes.

Ketogenesis step 1

HMG-CoA synthase (rate-limiting enzyme) converts acetyl-CoA → HMG-CoA.

Ketogenesis step 2

HMG-CoA → acetoacetate → β-hydroxybutyrate or spontaneously to acetone.

Ketone utilization

Used by brain, heart, and muscles for energy; especially important in fasting.