Anaplerotic roles of pyruvate carboxylase in mammalian tissues

Abstract

Pyruvate carboxylase (PC) catalyzes the ATP-dependent carboxylation of pyruvate to oxaloacetate. PC serves an anaplerotic role for the tricarboxylic acid cycle, when intermediates are removed for different biosynthetic purposes. In liver and kidney, PC provides oxaloacetate for gluconeogenesis. In adipocytes PC is involved in de novo fatty acid synthesis and glyceroneogenesis, and is regulated by the peroxisome proliferator-activated receptor-gamma, suggesting that PC is involved in the metabolic switch controlling fuel partitioning toward lipogenesis. In islets, PC is necessary for glucose-induced insulin secretion by providing oxaloacetate to form malate that participates in the 'pyruvate/malate cycle' to shuttle 3C or 4C between mitochondria and cytoplasm. Hyperglycemia and hyperlipidemia impair this cycle and affect glucose-stimulated insulin release. In astrocytes, PC is important for de novo synthesis of glutamate, an important excitatory neurotransmitter supplied to neurons. Transcriptional studies of the PC gene pinpoint some transcription factors that determine tissue-specific expression.

Prohibitin has an important role in adipocyte differentiation

“…The enzyme PC is present at a very unique position in metabolic pathways that has a critical role in providing substrates required for de novo triglycerides synthesis. 26,34 It is not unexpected that PC is upregulated B20-fold during adipocyte differentiation. 50 In addition, PC has an important role in the TCA cycle by regeneration of oxaloacetate, a driving force not only for pyruvate and fatty acid oxidation but also for glyceroneogenesis.…”

“…50 In addition, PC has an important role in the TCA cycle by regeneration of oxaloacetate, a driving force not only for pyruvate and fatty acid oxidation but also for glyceroneogenesis. 26,50 Previously, we have reported that PHB interacts with PC and inhibits insulin-induced glucose and fatty acid oxidation in adipose tissues. 25 However, the relevance of PHB and PC interaction in fatty acid synthesis and glyceroneogenesis remain to be determined.…”

“…23,24 In addition, we have shown that PHB interacts with pyruvate carboxylase (PC), 25 an important enzyme involved in de novo fatty acid synthesis and glyceroneogenesis. 26 Furthermore, PHB has been reported to be involved in Raf activation and to have an important role in MAPK/ERK signaling. 27 The PI3K/Akt and the MAPK/ERK signaling pathways are known to crosstalk with each other and have a critical role in adipocyte differentiation.…”

Comprehensive and quantitative proteome profiling of the mouse liver and plasma

“…Other proteins involved in major metabolic pathways of relevance to the liver and identified in both the liver and the plasma included proteins involved in gluconeogenesis and glycolysis and proteins involved in fatty acid metabolism. Examples include pyruvate carboxylase, which in the liver provides oxaloacetate for gluconeogenesis, 21 acyl-coenzyme A dehydrogenase, very long chain, which has been linked to fatty changes in the liver, 22 and xanthine oxidase, which has been hypothesized to be responsible for the increased lipid peroxidation associated with transplantation of steatotic livers. 23 Proteins associated with signaling pathways of relevance to liver biology (platelet-derived growth factor, interleukin-4, epidermal growth factor, and insulin receptor signaling pathways) were also identified among the proteins common to liver tissue and plasma.…”

Anaplerosis in cancer: Another step beyond the warburg effect

“…This biosynthetic process is stimulated by glucagon, which enhances pyruvate conversion to oxaloacetate. In a second step, phosphoenol pyruvate carboxykinase (PEPCK) uses the latter to produce phosphoenolpyruvate, which is required for the gluconeogenic pathway [32]. Nonetheless, PC possibly has an anaplerotic role in liver as demonstrated in a NMR analysis in which it was shown that pyruvate carboxylase is the major pathway for pyruvate influx into the Krebs cycle.…”