Abstract
Diets low in carbohydrates and proteins and enriched in fat stimulate the hepatic synthesis of ketone bodies (KB). These molecules are used as alternative fuel for energy production in target tissues. The synthesis and utilization of KB are tightly regulated both at transcriptional and hormonal levels. The nuclear receptor peroxisome proliferator activated receptor α (PPARα), currently recognized as one of the master regulators of ketogenesis, integrates nutritional signals to the activation of transcriptional networks regulating fatty acid β-oxidation and ketogenesis. New factors, such as circadian rhythms and paracrine signals, are emerging as important aspects of this metabolic regulation. However, KB are currently considered not only as energy substrates but also as signaling molecules. β-hydroxybutyrate has been identified as class I histone deacetylase inhibitor, thus establishing a connection between products of hepatic lipid metabolism and epigenetics. Ketogenic diets (KD) are currently used to treat different forms of infantile epilepsy, also caused by genetic defects such as Glut1 and Pyruvate Dehydrogenase Deficiency Syndromes. However, several researchers are now focusing on the possibility to use KD in other diseases, such as cancer, neurological and metabolic disorders. Nonetheless, clear-cut evidence of the efficacy of KD in other disorders remains to be provided in order to suggest the adoption of such diets to metabolic-related pathologies.
Highlights
The ketogenic diet (KD) is a dietary regimen intended to increase ketone bodies (KB) synthesis and utilization
Utilization of ketone bodies from non-hepatic tissues occurs in several tissues through ketolysis, and the rate-limiting enzyme is 3-oxoacid-transferase 1 (OXCT1), known as known as succinyl-CoA transferase (SCOT) or thiophorase
Recent evidence has shown that peroxisome proliferator activated receptor α (PPARα) plays a broader role during starvation and Ketogenic diets (KD) by inducing fibroblast growth factor 21 (FGF21) in the liver
Summary
The ketogenic diet (KD) is a dietary regimen intended to increase ketone bodies (KB) synthesis and utilization. Ketogenesis, mostly occurring in the liver, leads to the synthesis of acetoacetate (ACA) and β-hydroxybutyrate (βOHB), two main KB, from mitochondrial acetyl-CoA pool This pathway is usually active during fasting or prolonged exercise, when hepatic gluconeogenesis uses oxaloacetate from alanine, lactate and tricarboxylic acid (TCA) cycle to produce glucose. Utilization of ketone bodies from non-hepatic tissues occurs in several tissues through ketolysis, and the rate-limiting enzyme is 3-oxoacid-transferase 1 (OXCT1), known as known as succinyl-CoA transferase (SCOT) or thiophorase. These pathways are finely regulated at transcriptional and hormonal level. We will discuss possible mechanisms of action of KD and we will review current efforts to use KD in several diseases
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