Ketogenic diet

In the 1920’s it was observed that fasting was found to be beneficial to patients with difficult to control seizures. The ketogenic diet was designed as a treatment for these patients to mimic the biochemical changes associated with starvation. The ketogenic diet is a high-fat, low-protein, low-carbohydrate diet that depletes the patients carbohydrate and glycogen stores to cause a shift in the body’s metabolism toward a starvation state. When glucose levels are scarce in the circulating system, the body’s compensatory mechanism produces energy from the liver. Activation of hormone-sensitive lipases from adipose tissue mobilizes non-esterified fatty acids (NEFA), which provide substrates for the hepatic production of ketone bodies.

Production of ketones from the liver is explained in figure 1: Upon entrance of fatty acids into the hepatocyte from the blood, membrane-bound fatty acid acyl-CoA synthetases activate the fatty acids to become CoA esters – process known as CoA esterification. Following CoA esterification the metabolic pathways split dependent on the length of the fatty acid tail. Short- and medium-chain (MCT) acyl-CoAs can readily cross the inner and outer mitochondrial membranes and undergo β-oxidation into acetyl-CoA and acetoacetate. Long-chain acyl-CoAs can only readily cross the outer mitochondrial membrane, and subsequently must be converted to long-chain acylcarnitine for transport across the inner mitochondrial membrane. β-Oxidation in the mitochondria produces acetyl-CoA, which enters the TCA cycle for further production of ATP through oxidation. To achieve ketogenesis, the hepatic energy requirements must be met so that excess acetyl-CoA can be acted upon by thiolase. Thiolase condenses the two acetyl-CoAs to form acetoacetyl-CoA. Acetoacetyl-CoA is further condensed with acetyl-CoA by hydroxymethylglutyaryl-CoA synthase (HMG-CoA synthase) to form hydroxymethylglutaryl-CoA. Hydroxymethylglutaryl-CoA is then dissociated into acetoacetate and acetyl- CoA by hydroxymethylglutaryl-CoA lyase (HMG-CoA lyase). Most of the acetoacetate is reduced to β-hydroxybutyrate by the action of the enzyme β-hydroxybutyrate dehydrogenase, using NADH as a reductant. Following the reduction both acetoacetate and β-hydroxybutyrate are transported back through the mitochondrial membrane for exportation to the blood stream.

In contrast to normal brain cells, which evolved to metabolize ketone bodies for energy when glucose levels are reduced, most brain tumor cells are dependent on glycolysis for survival and are unable to metabolize ketone bodies for energy. Multiple researchers have demonstrated that the use of a ketogenic diet causes a reduction in blood glucose, an elevation in blood ketones and extends life in mouse models of malignant brain tumors. Armed with this knowledge and with the resurgence of tumor metabolism in the clinic, doctors were testing the efficacy of the ketogenic diet on cancer patients. Sparingly, case reports have been published showing the effectiveness of the ketogenic diet on a caseby- case basis. Their findings were similar in that the ketogenic therapies, which lower blood glucose levels while elevating ketone body levels, could be an effective non-toxic therapy for increasing progression free survival in patients with malignant brain tumors.