The pivotal role of pyruvate dehydrogenase kinases in metabolic flexibility

Abstract

Metabolic flexibility is the capacity of a system to adjust fuel (primarily glucose and fatty acids) oxidation based on nutrient availability. The ability to alter substrate oxidation in response to nutritional state depends on the genetically influenced balance between oxidation and storage capacities. Competition between fatty acids and glucose for oxidation occurs at the level of the pyruvate dehydrogenase complex (PDC). The PDC is normally active in most tissues in the fed state, and suppressing PDC activity by pyruvate dehydrogenase (PDH) kinase (PDK) is crucial to maintain energy homeostasis under some extreme nutritional conditions in mammals. Conversely, inappropriate suppression of PDC activity might promote the development of metabolic diseases. This review summarizes PDKs' pivotal role in control of metabolic flexibility under various nutrient conditions and in different tissues, with emphasis on the best characterized PDK4. Understanding the regulation of PDC and PDKs and their roles in energy homeostasis could be beneficial to alleviate metabolic inflexibility and to provide possible therapies for metabolic diseases, including type 2 diabetes (T2D).

Figure 1

PDC and PDKs occupy central positions in cellular energy metabolism. Fatty acid and glucose compete with each other for oxidation at the level of the PDC in mammals. PDC catalyzes the oxidative decarboxylation of pyruvate to form acetyl-CoA and thus links glucose metabolism and fatty acid metabolism. PDC can be phosphorylated by PDKs, which can be regulated by mitochondrial acetyl-CoA, NADH, pyruvate, ATP and nuclear transcription factors. ERRα: Estrogen related receptor α; FoxO: Forkhead box protein O; NEFA: Non-esterified fatty acid; PDC: Pyruvate dehydrogenase complex; PDKs: Pyruvate dehydrogenase kinases; PGC1α: PPARγ co-activator 1α; PPARs: Peroxisome proliferator-activated receptors; TG: Triglyceride; TCA: Tricarboxylic acid.

Figure 2

Transcriptional regulation pathways of PDK4 in different tissues under various nutritional states. Inactivation of PDC by up-regulation of PDK4 can switch glucose catabolism to fatty acid utilization. There are different transcriptional regulation pathways in skeletal muscle, liver, white adipose tissue and heart under various nutritional conditions (energy deprivation, high fat diet consumption, exercise, diseases, drugs). Akt/PKB: protein kinase B; AMPK: 5’-AMP-activated protein kinase; CD36: Cluster of differentiation 36; C/EBPβ: CCAAT/enhancer-binding protein β; eIF4E: Eukaryotic initiation factor 4E; ERRα: Estrogen related receptor α; FAT: Fatty acid transporter; FoxO1: Forkhead box protein O1; LXR: Liver X receptor; MAPK: p38 mitogen-activated protein kinase; PDC: Pyruvate dehydrogenase complex; PDK4: Pyruvate dehydrogenase kinase 4; PGC1α: PPARγ co-activator 1α; PPARs: Peroxisome proliferator-activated receptors; SHP: Small heterodimer partner; STAT5: Signal transducer and activator of transcription 5.