Figure 1.

Diagrammatic sketch of endogenous generation and consumption of BHB. Any factors that elevate the ratio of glucagon to insulin, such as fasting, prolonged exercise, insisting on a ketone diet, lactation, diabetes, or alcoholism, can accelerate the process of steatolysis and release lots of FFAs. The released FFAs are transported to the liver by albumin and are condensed with free CoASH in hepatocyte plasma. Then the condensed FFAs are transported into the mitochondrion by CPT1. The forage and concentrate englobed by ruminants are fermented into butyrate by rumen microbes and absorbed by colonocytes. The condensed FFAs and butyrate transported into the mitochondrion of hepatocytes or colonocytes are β-oxidated into Ac-CoA, two of which are further condensed into an AcAc-CoA, releasing a CoASH. The Ac-CoA and AcAc-CoA are then catalyzed to condense into HMG-CoA by mHMGCS2, encoded by a strictly spatiotemporally controlled gene (mHMGCS2). The HMG-CoA is cleaved into Ac-CoA and AcAc by HMGCL. The AcAc is reduced into D-BHB by BDH1 (consuming NADH and releasing NAD⁺) or spontaneously decarboxylated to volatile acetone and CO², released into the bloodstream by free diffusion and easily eliminated through the alveolar epithelial cells in the lung. Ac and AcAc are released into circulating blood. The D-BHB is transported across the mitochondrial intima through a yet-unknown mechanism and across the mitochondrial adventitia by SLC16A6 and released into the circulating blood. AcAc and BHB are absorbed by extrahepatic cells. BHB is oxidated to AcAc by BDH1 (consuming NAD⁺ and releasing NADH, a reversible reaction that also occurs in the generation process of BHB), and AcAc is activated into AcAc-CoA by SCOT1 (succinyl-CoA donates the CoA), and then split into Ac-CoA by mThiolase, consuming CoASH. The glucose derived from the glycogen is transported to and absorbed into the extrahepatic cells by GLUT. In the cytoplasm, the glucose is oxidated into pyruvate by glycolysis, inhibited by the BHB-derived Ac-CoA. Pyruvate is transported into the mitochondrion and then dehydrogenated to Ac-CoA by PDH, inhibited by the BHB-derived Ac-CoA. The BHB and pyruvate-derived Ac-CoA enter the TCA circle or act as signalling molecules. CoASH, coenzyme A; FFAs, free fatty acids; CPT1, carnitine palmitoyltransferase 1; FAO, fatty acids β-oxidation; Ac-CoA, acetyl-CoA; AcAc-CoA, acetoacetyl-CoA; mHMGCS2, mitochondrial 3-hydroxymethylglutaryl-coenzyme A synthase; HMG-CoA, hydroxymethylglutaryl-CoA; HMGCL, hydroxymethylglutaryl coenzyme A lyase; Ac, acetone; AcAc, acetoacetate; BHB, β-hydroxybutyrate; NADH/NAD⁺, nicotinamide adenine dinucleotide; SLC16A6, solute carrier family 16 member 6; MCT, monocarboxylate transporters; OXCT1, 3-oxoacid-CoA transferase 1; GLU, glucose; GLUT, glucose transporter; MPC, membrane permeation channel; CS, Citrate Synthase; TCA, tricarboxylic acid; ATP, adenosine triphosphate.