Ketone body metabolism + exogenous ketones

Category: biosynthesis

Overview

Ketogenesis (cross-link: ketone_body_synthesis) produces β-hydroxybutyrate (BHB), acetoacetate, and minor acetone under low-insulin / high-fatty-acid flux states. BHB is the dominant circulating ketone, metabolized in brain + heart + muscle to acetyl-CoA → TCA via BDH1 + SCOT (succinyl-CoA-3-ketoacid CoA transferase — absent in liver, which prevents the liver from oxidizing its own ketones). Exogenous ketone supplements bypass dietary keto: (1) BHB salts (Na/K/Ca/Mg-BHB) raise BHB to ~0.5-1 mM (sub-physiologic vs 1-5 mM with strict keto diet); (2) Ketone esters (HVMN Ketone-IQ / ΔG / 1,3-butanediol diester) achieve 2-4 mM. Claims: cognitive enhancement, endurance, neuroprotection, weight loss adjunct. Long-term clinical outcome data limited; mechanism plausible via mitochondrial uncoupling + HDAC inhibition + GPR109A signaling.

Organ Systems

• nervous
• musculoskeletal

Pathway Steps

1. acetyl-coa → beta-hydroxybutyrate — via HMG-CoA synthase + HMG-CoA lyase + BDH1 (hepatic ketogenesis); cross-link: ketone_body_synthesis. Hepatic ketogenesis (HMG-CoA synthase → HMG-CoA lyase → BDH1) runs when fasting/low-carb states flood mitochondria with acetyl-CoA while oxaloacetate is diverted to gluconeogenesis. The liver lacks SCOT, so it exports but cannot itself use ketones.
2. beta-hydroxybutyrate → acetyl-coa — via BDH1 + SCOT (extrahepatic tissues) → TCA. Extrahepatic tissues (brain, heart, muscle) reactivate ketones via BDH1 then SCOT (succinyl-CoA:3-ketoacid CoA transferase) to acetyl-CoA for the TCA cycle. The brain shifts to ketones for most of its fuel in prolonged fasting, sparing glucose and muscle protein.

Known Modulators

• bhb salt (substrate) — circulating BHB (salt-bound). racemic BHB ± enantiopure D-BHB; counter-ions (Na/K/Ca/Mg) drive their own electrolyte load
• l bhb (substrate) — L-BHB (non-physiologic enantiomer). L-isomer is poorly oxidized by BDH1 — most therapeutic interest is in D-BHB
• calcium bhb (substrate) — BHB (Ca counter-ion). Ca counter-ion form; ~30 mEq Ca per dose at typical 12 g BHB serving
• sodium bhb (substrate) — BHB (Na counter-ion). Na counter-ion; ~600 mg Na per 10 g BHB — HTN-sensitive patients consider
• potassium bhb (substrate) — BHB (K counter-ion). K counter-ion; renal-impairment + hyperkalemia caveat
• magnesium bhb (substrate) — BHB (Mg counter-ion). Mg counter-ion; GI tolerance varies
• butanediol 1 3 (substrate) — BHB precursor (alcohol → ketone via ADH/ALDH). 1,3-butanediol; ADH-converted to acetoacetate → BHB; ketone-ester building block
• butanediol ester (substrate) — BHB delivery (ester hydrolysis to BHB + BD). BD-BHB ester; raises BHB more durably than salts
• bd acetoacetate diester (substrate) — BHB + acetoacetate (diester). two-ester format; faster onset + balanced AcAc/BHB ratio
• ketone ester deltag (substrate) — BHB delivery (R-1,3-BD-BHB monoester ΔG). Veech-developed ester; military + endurance use; expensive
• bis hexanoyl bd (substrate) — BHB delivery (hexanoyl-BD ester). newer ester; aims for taste improvement + sustained kinetics
• mct c6 (substrate) — caproic acid → rapid hepatic ketogenesis (C6 MCT). fastest-oxidized MCT; raises BHB ~1-2 hr post-ingestion; GI tolerance limit
• mct c8 (substrate) — caprylic acid → ketogenesis (C8 MCT). most-studied ketogenic MCT (Brain Octane); ~2-fold BHB rise
• mct c10 (substrate) — capric acid → ketogenesis (C10 MCT). slower onset than C8; coconut-derived MCTs typically C8+C10 blend

References

• PMID 28826372