Figure 1: Pathways of Hepatic Ketogenesis and Myocardial Ketolysis.

Exogenous fats are absorbed through the gastrointestinal tract (specifically, medium chain triglycerides can be hydrolyzed by lipases to generate medium chain fatty acids). In addition, free fatty acids generated by adipolysis are circulated to the liver, where they undergo fatty acid oxidation in the hepatic mitochondria to produce acetyl CoA. Subsequent ketogenesis ultimately produces two mature ketone bodies: acetoacetate and β-hydroxybutyrate (β-OHB). Export from the hepatocytes and import into the cardiomyocyte is accomplished via monocarboxylate transporters. In cardiomyocyte mitochondria, ketolysis produces acetyl CoA that can be used in the tricyclic acid cycle. Notably, circulating ketones that are not oxidized by tissue can be 1) used for lipid or cholesterol synthesis (acetoacetate only) or 2) eliminated through the urine or exhaled as acetone (derived from decarboxylation of acetoacetate). Therapies used to achieve ketosis are noted in red. Abbreviations: ACAT, acetyl-CoA acetyltransferase; BHB, β-hydroxybutyrate; BDH, BHB dehydrogenase; HMGCL, HMG-CoA lyase; HMGCS2, HMG-CoA synthase; MCT, monocarboxylate transporter; SCOT, succinyl-CoA:3 oxoacid-CoA transferase; TCA; tricyclic acid.