Step 1 · Biochemistry

Fatty Acid & Ketone Body Metabolism

Name: Fatty Acid & Ketone Body Metabolism
Creator: Veli Bakalov, MD

Building, burning, and rationing fat when glucose runs out

Biochemistry·Bioenergetics & Lipid Metabolism·5 min read·8 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Fatty acids are synthesized in the cytosol from citrate-exported acetyl-CoA; acetyl-CoA carboxylase (biotin) is rate-limiting, activated by insulin and citrate, and fatty acid synthase makes palmitate using NADPH.
CPT-1 on the outer mitochondrial membrane is the rate-limiting gate for long-chain fatty acid oxidation and is inhibited by malonyl-CoA; short- and medium-chain fatty acids enter without carnitine.
Malonyl-CoA is the master switch: high in the fed state (build fat, block CPT-1), low in fasting (burn fat, make ketones).
Hypoketotic hypoglycemia after fasting = fatty acid oxidation defect; MCAD deficiency (AR, most common) shows dicarboxylic aciduria and high C8–C10 acylcarnitines and can mimic SIDS; treat by avoiding fasting.
CPT-2 deficiency: adult with exercise-induced muscle pain and myoglobinuria; primary carnitine deficiency: weakness, hypotonia, cardiomyopathy, hypoketotic hypoglycemia.
Mitochondrial HMG-CoA synthase is rate-limiting for hepatic ketogenesis (HMG-CoA reductase is for cholesterol); the liver lacks thiophorase (SCOT), so it exports but cannot use ketones, and RBCs can never use them.
High NADH/NAD+ (DKA, alcoholic ketoacidosis) favors beta-hydroxybutyrate, which nitroprusside misses; ketone readings may paradoxically rise as DKA improves.
DKA: glucose >250, give insulin + fluids; alcoholic ketoacidosis: glucose low/normal, give dextrose + thiamine + saline; all ketoacidoses raise the anion gap.

Fatty acid synthesis (fed state)

Location and carbon source. Fatty acid synthesis runs in the cytosol, mainly in liver, adipose tissue, and lactating breast. Acetyl-CoA made in mitochondria cannot cross the inner membrane, so it condenses with oxaloacetate and exits as citrate (the citrate shuttle); ATP-citrate lyase then regenerates cytosolic acetyl-CoA. The reducing power, NADPH, comes from the HMP shunt (pentose phosphate pathway) and malic enzyme.

SYtrate = SYnthesis: citrate carries carbons OUT of the mitochondrion to build fat. CARnitine = CARnage: carnitine carries fat IN to be burned.

Acetyl-CoA carboxylase (ACC). The rate-limiting enzyme of fatty acid synthesis. It uses biotin and CO₂ to carboxylate acetyl-CoA to malonyl-CoA — the same biotin-dependent chemistry as pyruvate carboxylase and propionyl-CoA carboxylase. ACC is activated by insulin and citrate and inhibited by glucagon and palmitoyl-CoA (end-product feedback).

Fatty acid synthase. A cytosolic multienzyme complex (containing pantothenic acid, B5, as phosphopantetheine) that adds 2-carbon units from malonyl-CoA to a growing chain until it releases palmitate (C16), consuming NADPH at each round. Elongation beyond C16 and desaturation happen later in the smooth ER.

Mitochondrial acetyl-CoA + OAA → citrateCitrate exits the mitochondrion
Citrate → acetyl-CoA (cytosol)ATP-citrate lyase
Acetyl-CoA → malonyl-CoAAcetyl-CoA carboxylase; biotin; rate-limiting
Malonyl-CoA → palmitate (C16)Fatty acid synthase; needs NADPH

Citrate shuttle to palmitate

Fatty acid oxidation (fasting state)

Carnitine shuttle. Long-chain fatty acids are first activated to acyl-CoA in the cytosol, but acyl-CoA cannot cross the inner mitochondrial membrane. CPT-1 on the outer membrane — the rate-limiting step of long-chain oxidation, inhibited by malonyl-CoA — forms acylcarnitine; carnitine-acylcarnitine translocase moves it across; CPT-2 on the inner membrane regenerates acyl-CoA in the matrix. Short- and medium-chain fatty acids enter without carnitine.

Cytosolic long-chain acyl-CoACannot cross the inner membrane
CPT-1 → acylcarnitineRate-limiting; blocked by malonyl-CoA
TranslocaseCarnitine-acylcarnitine exchange across the membrane
CPT-2 → acyl-CoA in the matrixEnters beta-oxidation

Carnitine shuttle

Beta-oxidation. In the mitochondrial matrix, each cycle clips 2 carbons and yields 1 acetyl-CoA, 1 NADH, and 1 FADH₂; palmitate takes 7 cycles to give 8 acetyl-CoA. Acetyl-CoA feeds the TCA cycle or, during fasting, ketogenesis, and it allosterically activates pyruvate carboxylase to support gluconeogenesis. Odd-chain fatty acids leave a final propionyl-CoA, which becomes succinyl-CoA (via B12-dependent methylmalonyl-CoA mutase) and is glucogenic. Very-long-chain fatty acids are shortened first in peroxisomes.

Malonyl-CoA decides build vs burn. Fed state (insulin): malonyl-CoA is high, fat is built, and CPT-1 is blocked, so newly made fat is not immediately burned. Fasting (glucagon): malonyl-CoA falls, CPT-1 opens, and beta-oxidation plus ketogenesis switch on. One molecule flips the whole system.

Fatty acid synthesis vs oxidation

Feature	Synthesis	Beta-oxidation
Location	Cytosol	Mitochondrial matrix
Hormonal state	Fed (insulin)	Fasting (glucagon)
Rate-limiting step	Acetyl-CoA carboxylase	CPT-1
Carrier	Citrate (carbons out)	Carnitine (acyl groups in)
Redox	Uses NADPH	Makes NADH and FADH₂
Malonyl-CoA	Product of the first step	Inhibits CPT-1

Fatty acid oxidation disorders

Hypoketotic hypoglycemia. The signature of a fatty acid oxidation defect: fat cannot be burned, so no ketones are made to spare glucose, and glucose is consumed quickly during a fast. Ketones are inappropriately low for the degree of hypoglycemia.

Carnitine and CPT defects. Primary (systemic) carnitine deficiency, a defect in cellular carnitine uptake, and CPT deficiencies block long-chain oxidation. Carnitine deficiency causes weakness, hypotonia, hypoketotic hypoglycemia, and cardiomyopathy; hepatic CPT-1 deficiency mainly causes fasting hypoketotic hypoglycemia. Primary carnitine deficiency responds to carnitine supplementation. CPT-2 deficiency classically presents in adults with exercise-induced muscle pain and myoglobinuria (rhabdomyolysis), often after prolonged exercise or fasting.

MCAD deficiency. Medium-chain acyl-CoA dehydrogenase deficiency is the most common fatty acid oxidation disorder (autosomal recessive). A fast, often during a viral illness, triggers vomiting, lethargy, and hypoketotic hypoglycemia that can progress to coma or sudden death mimicking SIDS. Labs show dicarboxylic aciduria and high C8–C10 acylcarnitines; newborn screening detects it. Treatment is avoiding fasting, with frequent carbohydrate feeds and IV dextrose during illness.

Classic fatty acid oxidation defects

Disorder	Typical patient	Key findings
MCAD deficiency	Infant or toddler after a fast	Hypoketotic hypoglycemia, vomiting, lethargy; dicarboxylic aciduria; ↑ C8–C10 acylcarnitines
CPT-2 deficiency	Adult after prolonged exercise or fasting	Muscle pain, myoglobinuria; fasting ketones usually normal (hypoketosis is the infantile form)
Primary carnitine deficiency	Child	Weakness, hypotonia, cardiomyopathy, hypoketotic hypoglycemia

Ketone bodies

Ketogenesis. In prolonged fasting and starvation (and in insulin deficiency), oxaloacetate is diverted to gluconeogenesis and acetyl-CoA from beta-oxidation piles up in hepatic mitochondria, where it is converted to ketone bodies. Mitochondrial HMG-CoA synthase is rate-limiting; HMG-CoA lyase then releases acetoacetate. (Cytosolic HMG-CoA reductase is the cholesterol enzyme.) Ketones export fat-derived fuel to brain and muscle.

The ketone bodies. The two real ketone bodies are acetoacetate and beta-hydroxybutyrate (BHB). Acetone is a minor, spontaneous breakdown product of acetoacetate that gives fruity breath. A high NADH/NAD⁺ ratio shifts the balance toward BHB. Ketone levels climb over the first days of a fast; after about 3 days of starvation the brain starts relying on ketones as a major fuel, and this adaptation keeps building over weeks.

Ketolysis. Peripheral tissues oxidize BHB back to acetoacetate, then thiophorase (succinyl-CoA–acetoacetate CoA transferase, SCOT) reactivates acetoacetate to acetoacetyl-CoA, which thiolase splits into acetyl-CoA. The liver lacks thiophorase, so it can make and export ketones but cannot consume them.

RBCs can never use ketones (no mitochondria) and depend on glucose; the brain can, after adaptation; the liver makes them but cannot use them.

Ketoacidoses and the nitroprusside trap

The three ketoacidoses

Feature	DKA	Starvation	Alcoholic ketoacidosis
Setting	Type 1 diabetes, insulin deficiency	Prolonged fasting	Recent binge, then poor intake or vomiting
Glucose	High (>250)	Low-normal	Low or normal
Ketosis	Marked	Mild	Marked; high NADH makes BHB predominate
Treatment	Insulin + IV fluids	Refeeding	Dextrose + thiamine + saline

All three raise the anion gap.

Nitroprusside misses BHB. The urine (or serum) nitroprusside reaction detects acetoacetate and acetone but not beta-hydroxybutyrate. In DKA and alcoholic ketoacidosis, high NADH makes BHB the predominant ketone, so nitroprusside can underestimate ketosis early on; measuring serum BHB directly avoids the trap.

As DKA is treated, NADH falls and BHB converts back to acetoacetate, so nitroprusside ketones may paradoxically rise even while the patient improves.