β-Hydroxybutyrat (BHB): the pathway in the body · Biomarker & Urine Analysis

β-Hydroxybutyrat (BHB) is part of the pathway “Ketone bodies”. This page shows the whole pathway; the station of β-Hydroxybutyrat (BHB) is highlighted.

Where this laboratory value sits: β-hydroxybutyrate — BHB, measurable in blood. The dehydrogenase BDH1 transfers hydrogen from NADH to acetoacetate, producing β-hydroxybutyrate. By quantity it is the largest ketone body in the blood. It serves brain, heart and muscle as fuel. Source 1, 2

In brief

Ketone bodies are small molecules that the liver builds from fatty acids; the largest share is β-hydroxybutyrate. Muscle, heart, kidney and brain turn them back into acetyl-CoA and feed it into the citrate cycle. Insulin slows their formation, fasting increases it.

The pathway step by step

Each station states what the compound does there. Three signs: ↑ supplies — builds up or makes available · ↓ depletes — inhibits, consumes or withholds · ↕ both, depending on amount. Behind it stands what the statement rests on: established physiology, observed in studies, or contested. The signs do not grade; they name the direction.

1. Fatty acids → Acetyl-CoA β-oxidation · carnitine (CPT1), NAD⁺, FAD In β-oxidation, the fatty acid is shortened step by step by two carbon atoms at a time; this yields acetyl-CoA. If a lot of it forms, more flows into ketogenesis. Source 4↕ both, depending on amount Acetyl-CoA from β-oxidation has two routes in the liver: into the citric acid cycle or into ketogenesis. If oxaloacetate is drawn off for glucose production, more of it flows into ketone bodies. established physiology Source 4, 1
   ⚖ When the balance tips

   too much — If acetyl-CoA builds up because the citric acid cycle does not absorb it, the excess goes via the thiolase and HMG-CoA synthase into ketone bodies.

   too little — If little acetyl-CoA forms, the citric acid cycle absorbs most of it, and hardly any is left for ketogenesis.

   established physiology · Source 1, 4

2. Acetyl-CoA → Acetoacetyl-CoA Thiolase A thiolase joins two acetyl-CoA molecules. This step is reversible and depends on how much acetyl-CoA is present. Plenty of acetyl-CoA drives it towards ketone bodies. Source 2↑ supplies Acetoacetyl-CoA is the first intermediate in which two acetyl units are joined. Because the step is reversible, the supply of acetyl-CoA determines which direction it runs. established physiology Source 2
   ⚖ When the balance tips

   too much — If a lot of acetoacetyl-CoA is present, HMG-CoA synthase takes it up as far as it is active; the thiolase splits the rest back into acetyl-CoA.

   too little — If little acetoacetyl-CoA forms, HMG-CoA synthase has no substrate, and the route to ketone bodies stays weak.

   established physiology · Source 2

3. Acetoacetyl-CoA → HMG-CoA HMG-CoA synthase 2 · acetyl-CoA Mitochondrial HMG-CoA synthase adds a further acetyl-CoA. This enzyme sets the pace of the whole pathway and is found mainly in the liver. Insulin reduces its production, glucagon and fasting increase it. Source 3, 2↑ supplies HMG-CoA synthase 2 is the control point of ketogenesis: insulin reduces its production, glucagon and fasting increase it. How much HMG-CoA forms thus sets how many ketone bodies the liver releases. established physiology Source 3, 1
   ⚖ When the balance tips

   too much — If a lot of synthase has been made, for example during long fasting, more acetyl-CoA flows into HMG-CoA, and the liver releases more ketone bodies into the blood.

   too little — If little synthase is present because insulin slows its production, acetyl-CoA stays in the citric acid cycle, and hardly any ketone bodies form.

   established physiology · Source 3

4. HMG-CoA → Acetoacetate HMG-CoA lyase HMG-CoA lyase splits off acetoacetate. A small part breaks down spontaneously into acetone, which is breathed out through the lungs. Acetoacetate is itself already a fuel for the tissues. Source 2, 1↕ both, depending on amount Acetoacetate is itself a fuel that the tissues use via SCOT. It is an acid; part of it breaks down into acetone, which is no longer used but breathed out. established physiology Source 1, 2
   ⚖ When the balance tips

   too much — If acetoacetate builds up, more of it breaks down spontaneously into acetone, which leaves via the breath; at the same time its acid groups bind buffer in the blood.

   too little — If little acetoacetate is present, BDH1 and SCOT have hardly any substrate, and the tissues draw their energy mainly from glucose and fatty acids.

   established physiology · Source 1, 2

5. Acetoacetate → β-hydroxybutyrate BDH1 · NADH The dehydrogenase BDH1 transfers hydrogen from NADH to acetoacetate, producing β-hydroxybutyrate. By quantity it is the largest ketone body in the blood. It serves brain, heart and muscle as fuel. Source 1, 2↕ both, depending on amount β-Hydroxybutyrate is the transport form: more stable than acetoacetate and a fuel for brain, heart and muscle. In cell culture and animal models it also acts as a signalling substance, for example on histone deacetylases and a receptor on fat cells. observed in studies Source 1
   ⚖ When the balance tips

   too much — If β-hydroxybutyrate builds up, it slows the release of fatty acids via a receptor on fat cells and thus its own supply; as an acid it binds buffer in the blood.

   too little — If there is little β-hydroxybutyrate in the blood, brain and heart draw their energy almost entirely from glucose and fatty acids; the brain absorbs ketone bodies in line with their blood level.

   observed in studies · Source 1

6. BHB in the cell → Acetoacetate BDH1 · NAD⁺ The same dehydrogenase BDH1 runs in reverse in the tissues: it removes hydrogen and passes it on to NAD⁺. This produces NADH for the respiratory chain. Source 2↑ supplies During the reconversion, β-hydroxybutyrate hands hydrogen to NAD⁺; this forms NADH, which enters the respiratory chain. The direction of the step follows the ratio of NADH to NAD⁺ in the cell. established physiology Source 2, 1
   ⚖ When the balance tips

   too much — If a lot of acetoacetate is present in the tissue, SCOT limits how fast it is processed further; more succinyl-CoA is used up in the process.

   too little — If little NAD⁺ is free, for example because the respiratory chain is at capacity, the reconversion runs more slowly, and β-hydroxybutyrate stays unused for longer.

   established physiology · Source 2, 1

7. Acetoacetate → Acetoacetyl-CoA SCOT · succinyl-CoA The enzyme SCOT transfers a CoA group from succinyl-CoA to acetoacetate. This step occurs in almost all tissues, but not in the liver. So the liver does not use up its own ketone bodies. Source 2, 1↕ both, depending on amount SCOT makes acetoacetate usable and draws succinyl-CoA from the citric acid cycle to do so. Because the liver has no SCOT, it does not use its own ketone bodies but passes them on to other organs. established physiology Source 2, 1
   ⚖ When the balance tips

   too much — If a lot of acetoacetate runs through SCOT, more succinyl-CoA is drawn from the citric acid cycle, and the cell gains more acetyl-CoA from ketone bodies.

   too little — If SCOT activity is low, acetoacetate stays unused in the tissue and returns to the blood; ketone bodies then accumulate there.

   established physiology · Source 2, 1

8. Acetoacetyl-CoA → Acetyl-CoA Thiolase · CoA A thiolase splits acetoacetyl-CoA into two acetyl-CoA. From here on the fuel is the same as that from sugar and fat. Source 2↑ supplies The thiolase yields two acetyl-CoA, the same form that also arises from glucose and fatty acids. From here on, it can no longer be told where the fuel came from. established physiology Source 2, 1
   ⚖ When the balance tips

   too much — If a lot of acetyl-CoA forms from ketone bodies, the cell breaks down less glucose; the fuels replace one another.

   too little — If the thiolase yields little acetyl-CoA, the fuel for the citric acid cycle comes from glucose and fatty acids.

   established physiology · Source 1

9. Acetyl-CoA → Citric acid cycle Acetyl-CoA enters the citric acid cycle. The electrons gained there drive ATP production in the respiratory chain. In this way ketone bodies become ATP. Source 1↑ supplies In the citric acid cycle, acetyl-CoA is broken down completely to CO₂; the electrons pass as NADH and FADH₂ into the respiratory chain, which uses them to make ATP. established physiology Source 1
   ⚖ When the balance tips

   too much — If more acetyl-CoA arrives than the cycle and respiratory chain can process, NADH and ATP rise in the cell and slow the enzymes of the cycle.

   too little — If little acetyl-CoA arrives, the cycle runs more slowly, and the respiratory chain makes less ATP.

   established physiology · Source 1

Further stations

• Fatty acids — from adipose tissue When little sugar is available, fat cells release fatty acids into the blood. The liver absorbs them and moves them into the mitochondria via the carnitine system. Insulin slows this release. Source 1, 4↑ supplies Fatty acids are the raw material of ketone bodies. Insulin slows their release from fat cells, glucagon and fasting increase it; the balance of these hormones thus sets how much starting material reaches the liver. established physiology Source 1, 4
  ⚖ When the balance tips

  too much — If more fatty acids reach the liver than β-oxidation breaks down, the liver converts the excess into triglycerides and stores it or releases it in lipoproteins.

  too little — If few fatty acids arrive, for example because insulin slows their release, the liver makes hardly any ketone bodies; the tissues then draw their energy mainly from glucose.

  established physiology · Source 1, 4

• BHB in the cell — uptake via MCT1 Muscle, heart, kidney and brain absorb β-hydroxybutyrate from the blood via monocarboxylate transporters. The liver itself does not have the enzyme to use it again. The more of it is in the blood, the more they absorb. Source 1↑ supplies In muscle, heart, kidney and brain, β-hydroxybutyrate is a fuel that partly replaces glucose. Uptake via monocarboxylate transporters rises with the blood level. established physiology Source 1
  ⚖ When the balance tips

  too much — If more β-hydroxybutyrate arrives, the tissues use more of it; transporters and SCOT set the upper limit, and part of it leaves via the kidneys.

  too little — If little arrives, the tissues cover their needs from glucose and fatty acids; the brain then relies almost entirely on glucose.

  established physiology · Source 1, 2

Cofactors in this pathway

• Carnitine — Carrier with which CPT1 brings the fatty acids into the mitochondrion; without it few fatty acids reach β-oxidation Source 4In the ORY catalogue as a laboratory value: Carnitin
• Coenzyme A — Carries the acetyl and acyl groups all the way from fatty acid to ketone body; if it is scarce, the route stalls Source 1, 2
• NAD⁺ — Hydrogen carrier in β-oxidation and at BDH1, which interconverts acetoacetate and BHB, depending on the NADH level Source 4, 1In the ORY catalogue as a laboratory value: NAD⁺ (Nicotinamidadenindinukleotid)
• Vitamin B2 (FAD) — Flavin cofactor of the acyl-CoA dehydrogenases in β-oxidation; without FAD, fat breakdown stalls Source 4
• Succinyl-CoA — In tissues it hands its CoA group to acetoacetate; the enzyme SCOT performs this step, which uses it up Source 2
• Leucine — Amino acid whose breakdown reaches acetoacetate through the same HMG-CoA lyase; so protein also yields ketone bodies Source 5, 2In the ORY catalogue as a laboratory value: Leucin

Sources

1. Puchalska P, Crawford PA. Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics. Cell Metab 2017 · PubMed 28178565
2. Fukao T, Mitchell G, Sass JO et al. Ketone body metabolism and its defects. J Inherit Metab Dis 2014 · PubMed 24706027
3. Hegardt FG. Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: a control enzyme in ketogenesis. Biochem J 1999 · PubMed 10051425
4. Adeva-Andany MM, Carneiro-Freire N et al. Mitochondrial β-oxidation of saturated fatty acids in humans. Mitochondrion 2019 · PubMed 29551309
5. Arnedo M, Latorre-Pellicer A, Lucia-Campos C et al. More Than One HMG-CoA Lyase: The Classical Mitochondrial Enzyme Plus the Peroxisomal and the Cytosolic Ones. Int J Mol Sci 2019 · PubMed 31817290

Whole pathway: Ketone bodies

Related pathways

• Cholesterol and lipoproteins — hmg-coa
• Digestion and absorption — fatty acids
• Alanine — NAD⁺ (Nicotinamidadenindinukleotid), Leucin
• Trans fatty acids — Carnitin, NAD⁺ (Nicotinamidadenindinukleotid)
• Triglycerides — Carnitin, NAD⁺ (Nicotinamidadenindinukleotid)

As of 2026-09-16. Draft written by Claude to schema v2; sources checked in PubMed; expert approval pending
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