Ketogenic Diet and Ketone Bodies against Ischemic Injury: Targets, Mechanisms, and Therapeutic Potential

Abstract

The ketogenic diet (KD) has been used as a treatment for epilepsy since the 1920s, and its role in the prevention of many other diseases is now being considered. In recent years, there has been an intensive investigation on using the KD as a therapeutic approach to treat acute pathologies, including ischemic ones. However, contradictory data are observed for the effects of the KD on various organs after ischemic injury. In this review, we provide the first systematic analysis of studies conducted from 1980 to 2022 investigating the effects and main mechanisms of the KD and its mimetics on ischemia-reperfusion injury of the brain, heart, kidneys, liver, gut, and eyes. Our analysis demonstrated a high diversity of both the composition of the used KD and the protocols for the treatment of animals, which could be the reason for contradictory effects in different studies. It can be concluded that a true KD or its mimetics, such as β-hydroxybutyrate, can be considered as positive exposure, protecting the organ from ischemia and its negative consequences, whereas the shift to a rather similar high-calorie or high-fat diet leads to the opposite effect.

Keywords: acetoacetate; beta-hydroxybutyrate; ischemia; ketogenic diet; ketone bodies; reperfusion.

Figure 1

The metabolism of ketone bodies. Ketone bodies are produced in mitochondria of hepatocytes during ketogenesis, whereas utilization of ketone bodies takes place in the mitochondria of peripheral extrahepatic tissues during ketolysis. AcAc—acetoacetate; BDH1—D-β-hydroxybutyrate dehydrogenase; BHB—β-hydroxybutyrate; CPT1—carnitine palmitoyltransferase 1; ETC—electron transport chain; HMG-CoA—3-hydroxy-3-methylglutaryl-CoA; MCT1/2—monocarboxylate transporter 1/2; MPC—mitochondrial pyruvate carrier; SCOT—succinyl-CoA:3-ketoacid CoA transferase; TCA cycle—tricarboxylic acid cycle.

Figure 2

Possible mechanisms of the beneficial effects of KD and ketone bodies on IR injury. Red arrows indicate the effects mediated by ischemia and reperfusion, while black arrows specify the effects mediated by KD. AMPK—AMP-activated protein kinase; DAMPs, damage-associated molecular patterns; Drp1—dynamin-related protein 1; FoxO3a—forkhead box protein O3a; IL-(1β, 6, 18)—interleukin-(1β, 6, 18); HDAC, histone deacetylases; HIF-1α—hypoxia-inducible factor-1α; HO-1—heme oxygenase-1; mPTP—mitochondrial permeability transition pore; LC3—microtubule-associated protein 1A/1B-light chain 3; NLRP3—NOD-, LRR-, and pyrin domain-containing protein 3; NF-κB -nuclear factor-κB; Nrf2—nuclear respiratory factor 2; ROS, reactive oxygen species; SOD, superoxide dismutase; TNF-α—tumor necrosis factor-α.