Lipid Metabolism

BCH 100 — Introductory Biochemistry · Dr. Radi

build Jul 17 · 15:14 · CC BY-NC-SA 4.0 · owned figures (RDKit / matplotlib / PyMOL)
Dr. Radi

By the end of this unit, you can…

  • Describe lipoproteins (chylomicrons, VLDL, LDL, HDL) and how fat and cholesterol move through the blood
  • Trace fat mobilization — lipolysis to glycerol + free fatty acids, activation to acyl-CoA, and the carnitine shuttle into the mitochondrion
  • Walk the four steps of β-oxidation with its enzymes and FADH₂/NADH/acetyl-CoA yield, and calculate the ATP from oxidizing a fatty acid
  • Explain ketone-body synthesis and use as a fasting fuel, and distinguish physiological ketosis from diabetic ketoacidosis
  • Outline fatty-acid synthesis (acetyl-CoA carboxylase, fatty acid synthase, the citrate shuttle) and the reciprocal regulation that keeps synthesis and breakdown from running at once
Dr. Radi

Today's route 🗺️

  1. Lipoproteins: Fat in the Blood
  2. Getting Fat Ready to Burn
  3. β-Oxidation
  4. Ketone Bodies
  5. Building Fat
Dr. Radi

1 · Lipoproteins: Fat in the Blood

"Fat and water don't mix — so how does a greasy meal travel through watery blood? In tiny cargo ships called lipoproteins."

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Fat can't swim — so it takes a boat

You just ate a greasy meal. Now that fat has to cross your watery blood to reach your muscles and fat stores — and oil doesn't dissolve in water. The fix is a lipoprotein: a little droplet of oily cargo (triglycerides + cholesteryl esters) wrapped in a single layer of phospholipids — heads out, facing the water — plus some cholesterol and apolipoproteins. Those apoproteins are the address labels that tell each particle where to dock.

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Four ships, sorted by density

There isn't one lipoprotein — there are four, and the way to keep them straight is density. The more fat a particle carries, the bigger and lighter it is; the more protein, the smaller and denser. Chylomicrons are huge, greasy, and light (dietary fat). VLDL is the liver's fat-export truck. LDL is denser and delivers cholesterol. HDL is the smallest and densest. Their names literally are their densities — Very-Low, Low, and High-Density Lipoprotein.

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Where it all goes: three routes

Follow the fat and it makes sense. Route 1 (dietary): your gut packs a meal's fat into chylomicrons and ships it to muscle and fat tissue. Route 2 (liver's own): your liver loads fat and cholesterol into VLDL, which sheds triglyceride and shrinks into LDL as it delivers cholesterol around the body. Route 3 (cleanup): HDL cruises the tissues picking up excess cholesterol and carries it back to the liver — the only route running in reverse.

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"Good" cholesterol vs "bad"

Now the famous part. LDL drops cholesterol off in your tissues — and when there's too much, it seeps into artery walls, where it's oxidized, triggers inflammation, and builds a plaque that narrows the vessel (atherosclerosis, shown here). That's why LDL is the "bad" cholesterol. HDL does the opposite — it hauls cholesterol away to the liver, so it's the "good" one. Same molecule, cholesterol; the difference is which direction it's traveling.

Coronary artery plaque: BruceBlaus, CC BY 3.0 (Wikimedia Commons)
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2 · Getting Fat Ready to Burn

"Before a fatty acid can be burned it has to be released, tagged with CoA, and smuggled into the mitochondrion. Three gates before the fire."

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Step one: unlock the fat

Fat is the body's biggest fuel tank — pound for pound it stores more than twice the energy of carbohydrate, and you carry far more of it. But it's locked away as triglyceride in your fat cells. To use it, an enzyme called lipase hydrolyzes each triglyceride into glycerol + three free fatty acids. The glycerol slips into glycolysis (as DHAP). The fatty acids — where nearly all the energy is — head for the mitochondria to be burned.

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Step two: clip on a CoA handle

A free fatty acid is unreactive — the cell can't do anything with it until it's activated. The enzyme acyl-CoA synthetase attaches coenzyme A, turning the fatty acid into a fatty acyl-CoA. This costs one ATP — but broken all the way to AMP + PPᵢ, so it's really two high-energy bonds. And because the PPᵢ is immediately hydrolyzed, activation is irreversible: once you've committed a fatty acid, there's no going back.

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Step three: the carnitine shuttle

Now a problem: long-chain acyl-CoA can't cross the inner mitochondrial membrane. So the cell ferries it: CPT1 swaps CoA for carnitine (→ acyl-carnitine), a translocase carries it across, and CPT2 swaps carnitine back for CoA — regenerating acyl-CoA in the matrix, right where β-oxidation happens. CPT1 is the rate-limiting gate: the cell's main control point for burning fat.

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Why this is the marathoner's engine

This whole pathway is what powers endurance. In a long run, once the quick sugar is gone, your muscles switch to burning fat — which means running fatty acids through activation, the carnitine shuttle, and β-oxidation, hour after hour. It's also why the shuttle matters clinically: people with CPT II deficiency can't move fat into the mitochondria, so prolonged exercise or fasting triggers muscle pain and breakdown — their cells simply can't reach their biggest fuel tank.

Marathon finisher: Shixart1985, CC BY 2.0 (Wikimedia Commons)
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3 · β-Oxidation

"Now the fire. A fatty acid is chewed off two carbons at a time — the same four reactions, over and over — pouring out NADH, FADH₂, and acetyl-CoA."

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The spiral that eats a fatty acid

Once a fatty acyl-CoA is in the matrix, it's burned by β-oxidation — named because the action happens at the β-carbon (the third carbon, counting the carbonyl as one). It's a spiral: the same four reactions — oxidize, hydrate, oxidize, cut — run over and over. Each lap clips off the last two carbons as acetyl-CoA and hands you one FADH₂ and one NADH, leaving a fatty acid two carbons shorter to go around again.

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Step ①: oxidation → makes FADH₂

First, acyl-CoA dehydrogenase pulls two hydrogens off the α- and β-carbons, creating a trans double bond between them (a trans-Δ² -enoyl-CoA). Those electrons are caught by FAD, making FADH₂ — worth ~1.5 ATP downstream. This is the step that MCAD (medium-chain) does; keep an eye on it — it comes back at the end of the lecture.

This turn so far: 1 FADH₂

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Step ②: hydration

Next, enoyl-CoA hydratase adds a molecule of water across that new double bond, parking a hydroxyl group on the β-carbon. No electrons are harvested here — it's a setup move, converting the double bond into a β-hydroxyl so the next enzyme has something to oxidize. The product is 3-hydroxyacyl-CoA.

This turn so far: 1 FADH₂

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Step ③: oxidation → makes NADH

Now 3-hydroxyacyl-CoA dehydrogenase oxidizes that β-hydroxyl into a β-keto group — turning the carbon into a ketone. The two electrons go to NAD⁺, making NADH — worth ~2.5 ATP. The molecule is now a 3-ketoacyl-CoA, primed with a carbonyl exactly where the chain is about to be cut.

This turn so far: 1 FADH₂ · 1 NADH

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Step ④: thiolysis → releases acetyl-CoA

Finally, thiolase breaks the bond between the α- and β-carbons, and a fresh CoA grabs the loose end. Out pops acetyl-CoA (the two-carbon piece), and what's left is an acyl-CoA two carbons shorter — ready to re-enter the spiral at step ①. One lap: 1 FADH₂, 1 NADH, 1 acetyl-CoA.

One full turn: 1 FADH₂ · 1 NADH · 1 acetyl-CoA · chain −2 C

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Add it up: why fat is such rich fuel

Take palmitate (C16). It goes around 7 times — producing 8 acetyl-CoA, 7 FADH₂, and 7 NADH. Send the acetyl-CoA through the TCA cycle and the carriers through the electron transport chain, subtract the 2 ATP you spent activating it up front, and you clear about 106 ATP — versus roughly 32 from a glucose. Fat stores more energy and releases more of it per molecule.

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When step ① is broken

That first enzyme comes in chain-length versions — long, medium, and short. MCAD deficiency (medium-chain acyl-CoA dehydrogenase) is one of the most common inherited metabolic disorders, and it's dangerous precisely because fat is a backup fuel: as long as a baby eats often, glucose covers everything. But during a fast or an illness, when the body must switch to burning fat, an MCAD-deficient infant can't — blood sugar crashes and they can become critically ill. That's why nearly every newborn is screened for it at birth.

Sleeping newborn: esudroff, CC0 (Wikimedia Commons)
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4 · Ketone Bodies

"Burn fat fast enough and acetyl-CoA piles up. The liver packages the overflow into ketone bodies — a water-soluble fuel even your brain can run on."

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Plan B for acetyl-CoA

β-oxidation is fast — and in a long fast or on a low-carb diet, it floods the mitochondrion with acetyl-CoA faster than the TCA cycle can burn it (the oxaloacetate it needs is being siphoned off to make glucose). So the liver does something clever with the excess: it condenses acetyl-CoA — two at a time, through an HMG-CoA intermediate — into ketone bodies. It's an overflow valve, turning a traffic jam of acetyl-CoA into a fuel it can ship out.

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Meet the three ketone bodies

There are three, and despite the name only two are truly "keto." Acetoacetate is the parent — a simple β-keto acid. Reduce it (using NADH) and you get β-hydroxybutyrate, actually the most abundant one in blood (and, confusingly, not a ketone at all — it's an alcohol). Let acetoacetate sit and it slowly loses CO₂ to become acetone — the one you can't use, so you breathe it out (that "fruity" breath).

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The fuel your brain can actually use

Here's why ketones matter. Your brain normally runs on glucose and can't burn fatty acids — they don't cross into it. So in a long fast, what keeps you thinking? Ketone bodies. The liver makes them but can't burn them itself; it ships them through the blood to the brain, heart, and muscle, which convert them back to acetyl-CoA and feed the TCA cycle. In prolonged starvation, ketones can supply up to two-thirds of the brain's energy — sparing precious glucose.

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Ketosis vs. ketoacidosis

Ketones are acids, so the difference between helpful and dangerous is how many. Physiological ketosis — from fasting, keto diets, or long exercise — is controlled: insulin still reins in fat release, ketones rise modestly, and your blood buffers hold pH at 7.4. Diabetic ketoacidosis (DKA) is the runaway version: in type-1 diabetes with no insulin, lipolysis goes unchecked, ketones flood the blood faster than buffers can cope, and blood pH crashes — a life-threatening emergency. Same molecules; a matter of degree.

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5 · Building Fat

"Making fat is burning it run backwards — different place, different carriers, different cofactor. And a single molecule decides whether you build or burn."

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Building fat: the plan

When you have more fuel than you need, you store it — and that means making fatty acids. The build happens in the cytosol (not the mitochondrion), and it needs two things: carbon, delivered as acetyl-CoA, and reducing power, delivered as NADPH. The committed step is acetyl-CoA carboxylase (ACC), which spends ATP and CO₂ to make malonyl-CoA. Then fatty acid synthase adds two carbons at a time — seven rounds — to build palmitate (C16).

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Getting the carbon out: the citrate shuttle

There's a logistics problem: acetyl-CoA is made inside the mitochondrion, but fat is built in the cytosol — and acetyl-CoA can't cross the inner membrane. The trick: in the matrix, acetyl-CoA is joined to oxaloacetate to make citrate (yes, the TCA intermediate), which can cross out. In the cytosol, ATP-citrate lyase splits citrate back into acetyl-CoA + oxaloacetate. The acetyl-CoA feeds synthesis; the oxaloacetate cycles home, generating some NADPH on the way.

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Burning vs. building: mirror images

Fatty-acid synthesis is not just β-oxidation in reverse gear — but it rhymes with it, point for point. Different compartment (cytosol vs. mitochondria), different carrier (ACP vs. CoA), and — crucially — a different cofactor: breakdown makes NADH and FADH₂ to burn for ATP, while synthesis spends NADPH to build. One removes acetyl-CoA two carbons at a time; the other adds it (as malonyl-CoA). Learn one and you nearly know the other.

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The switch: reciprocal regulation

Building and burning fat at the same time would just waste ATP in a futile cycle — so the cell makes sure only one runs at a time. The elegant part is the switch: malonyl-CoA, the very first building block of synthesis, also blocks CPT1, the gate into β-oxidation. So when you're fed (insulin, high citrate), ACC fires, malonyl-CoA rises, synthesis runs, and burning is shut off. When you're fasting (glucagon, epinephrine), ACC is switched off, malonyl-CoA falls, CPT1 opens, and you burn.

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Beyond palmitate

Fatty acid synthase only makes one product — palmitate (C16). Everything else is remodeling, done mostly in the endoplasmic reticulum: enzymes elongate the chain and desaturate it (adding double bonds, e.g. making oleate). Those tailored fatty acids then get built into triglycerides, phospholipids, cholesterol, and signaling lipids. One catch: humans can't add double bonds past the Δ9 position — which is exactly why ω-3 and ω-6 fats are essential and must come from your diet.

Dr. Radi

Can you…?

  • ☐ describe lipoproteins (chylomicrons, VLDL, LDL, HDL) and how fat and cholesterol move through the blood?
  • ☐ trace fat mobilization — lipolysis to glycerol + free fatty acids, activation to acyl-CoA, and the carnitine shuttle into the mitochondrion?
  • ☐ walk the four steps of β-oxidation with its enzymes and FADH₂/NADH/acetyl-CoA yield, and calculate the ATP from oxidizing a fatty acid?
  • ☐ explain ketone-body synthesis and use as a fasting fuel, and distinguish physiological ketosis from diabetic ketoacidosis?
  • ☐ outline fatty-acid synthesis (acetyl-CoA carboxylase, fatty acid synthase, the citrate shuttle) and the reciprocal regulation that keeps synthesis and breakdown from running at once?

If any box stays empty, the practice site has a drill for it. 🧪

Dr. Radi