The role of phosphoenolpyruvate carboxykinase in neuronal steroidogenesis under acute inflammation

Sadasivam, Mohanraj; Ramatchandirin, Balamurugan; Balakrishnan, Sivasangari; Selvaraj, K; Prahalathan, Chidambaram

doi:10.1016/j.gene.2014.09.043

Cited by 15 publications

(8 citation statements)

References 20 publications

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“…PEPCK-C also is a negative marker of colon cancer (11) and alleviates renal tubu- lar acidosis (9). In model organisms, PEPCK-C supports adaptive response and survival under inflammation (85), osmotic stress (86), and oxidative stress (this study). These metabolic and physiological roles of PEPCK-C indicate that it is a major metabolic adaptor of organisms that promotes health and longevity.…”

Section: Discussionmentioning

confidence: 79%

Reciprocal Changes in Phosphoenolpyruvate Carboxykinase and Pyruvate Kinase with Age Are a Determinant of Aging in Caenorhabditis elegans

Yuan¹,

Hakimi²,

Kao³

et al. 2016

Journal of Biological Chemistry

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Aging involves progressive loss of cellular function and integrity, presumably caused by accumulated stochastic damage to cells. Alterations in energy metabolism contribute to aging, but how energy metabolism changes with age, how these changes affect aging, and whether they can be modified to modulate aging remain unclear. In locomotory muscle of post-fertile Caenorhabditis elegans, we identified a progressive decrease in cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), a longevity-associated metabolic enzyme, and a reciprocal increase in glycolytic pyruvate kinase (PK) that were necessary and sufficient to limit lifespan. Decline in PEPCK-C with age also led to loss of cellular function and integrity including muscle activity, and cellular senescence. Genetic and pharmacologic interventions of PEPCK-C, muscle activity, and AMPK signaling demonstrate that declines in PEPCK-C and muscle function with age interacted to limit reproductive life and lifespan via disrupted energy homeostasis. Quantifications of metabolic flux show that reciprocal changes in PEPCK-C and PK with age shunted energy metabolism toward glycolysis, reducing mitochondrial bioenergetics. Last, calorie restriction countered changes in PEPCK-C and PK with age to elicit antiaging effects via TOR inhibition. Thus, a programmed metabolic event involving PEPCK-C and PK is a determinant of aging that can be modified to modulate aging.Aging is characterized by the progressive decline in cellular function and integrity that leads to disease vulnerability and eventually death of organisms (1). The leading proposed cause of decline in cellular function and integrity with age is the accumulation of stochastic damage of molecules and organelles by reactive molecules, such as reactive oxygen species (ROS). Whether ROS are detrimental to organisms and whether ROS limit lifespan, however, are in debate (2).Energy metabolism supplies ATP for cellular function and maintenance. Alterations in energy metabolism are linked to the aging process and aging-associated diseases (3). In model organisms, environmental and genetic factors that change energy metabolism, such as calorie restriction (CR) (4), inhibition of target of rapamycin (TOR) (5), and 5Ј AMP kinase (AMPK) (6) are determinants of longevity. A large body of aging research has been focusing on the signaling of CR, TOR inhibition, and AMPK in regulating longevity. The exact alterations in energy metabolism that occur with age, how these changes impact aging, and whether they can be modified to modulate aging are understudied and remain poorly understood, largely due to the intrinsic complexity of energy metabolism, and the indirect impact of these longevity paradigms on energy metabolism. This impedes the understanding of aging mechanisms and the development of mechanism-based strategies to modulate aging.A key regulation of energy metabolism at the cellular level is the reciprocal changes of PK and PEPCK-C (7). Whether this regulation of cellular energy metabolism contributes to organismal aging is...

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Section: Discussionmentioning

confidence: 79%

Reciprocal Changes in Phosphoenolpyruvate Carboxykinase and Pyruvate Kinase with Age Are a Determinant of Aging in Caenorhabditis elegans

Yuan¹,

Hakimi²,

Kao³

et al. 2016

Journal of Biological Chemistry

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“…The cataplerotic role of PEPCK-C has been recognized in cell proliferation [ 60 ], and adaptive response to stresses, such as acidosis [ 61 ], inflammation [ 62 ], and osmotic stress [ 30 ]. Under these circumstances, PEPCK-C supports the synthesis of ribose, glucose, steroid, and glycerol from amino acids and other non-carbohydrates.…”

Section: Reciprocal Changes In Pepck-c and Pk Profoundly Impact Agingmentioning

confidence: 99%

Reprogramming of energy metabolism as a driver of aging

et al. 2016

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Aging is characterized by progressive loss of cellular function and integrity. It has been thought to be driven by stochastic molecular damage. However, genetic and environmental maneuvers enhancing mitochondrial function or inhibiting glycolysis extend lifespan and promote healthy aging in many species. In post-fertile Caenorhabditis elegans, a progressive decline in phosphoenolpyruvate carboxykinase with age, and a reciprocal increase in pyruvate kinase shunt energy metabolism from oxidative metabolism to anaerobic glycolysis. This reduces the efficiency and total of energy generation. As a result, energy-dependent physical activity and other cellular functions decrease due to unmatched energy demand and supply. In return, decrease in physical activity accelerates this metabolic shift, forming a vicious cycle. This metabolic event is a determinant of aging, and is retarded by caloric restriction to counteract aging. In this review, we summarize these and other evidence supporting the idea that metabolic reprogramming is a driver of aging. We also suggest strategies to test this hypothesis

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“…It is mainly involved in important life activities such as cell proliferation and differentiation, tumorigenesis and apoptosis, body inflammatory response, and so on through the regulation of gene transcription of target cells ( Ramji and Foka, 2002 ). PCK1 and EFNA1 have been found to be involved in important life activities such as cell proliferation and apoptosis, tumor angiogenesis, malignant cell events, and invasiveness ( Sadasivam et al, 2014 ), and their expression is upregulated in a variety of tumors [such as colorectal cancer ( Shi et al, 2012 )]. However, whether there is a link between transcription factors and super-enhancer–driven genes is still unknown.…”

Section: Discussionmentioning

confidence: 99%

Nintedanib Alleviates Experimental Colitis by Inhibiting CEBPB/PCK1 and CEBPB/EFNA1 Pathways

et al. 2022

Front. Pharmacol.

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The super-enhancer, a cluster of enhancers with strong transcriptional activity, has become one of the most interesting topics in recent years. This study aimed to investigate pathogenic super-enhancer–driven genes in IBD and screen therapeutic drugs based on the results. In this study, through the analysis of differentially expressed genes in colitis patients from the GEO database and the analysis of the super-enhancer–associated database, we found that the super-enhancer pathogenic genes PCK1 and EFNA1 were simultaneously regulated by transcription factor CEBPB through two super-enhancers (sc-CHR20-57528535 and sc-CHR1-155093980). Silencing CEBPB could significantly inhibit the expression of PCK1 and EFNA1 and enhance the expression of epithelial barrier proteins claudin-1, occludin, and ZO-1. In LPS-induced Caco-2 cells, drugs commonly used in clinical colitis including tofacitinib, oxalazine, mesalazine, and sulfasalazine inhibited mRNA levels of CEBPB, PCK1, and EFNA1. In the drug screening, we found that nintedanib significantly inhibited the mRNA and protein levels of CEBPB, PCK1, and EFNA1. In vivo experiments, nintedanib significantly alleviated DSS-induced colitis in mice by inhibiting CEBPB/PCK1 and CEBPB/EFNA1 signaling pathways. At the genus level, nintedanib improved the composition of the gut microbiota in mice with DSS-induced experimental colitis. In conclusion, we found that PCK1 and EFNA1 are highly expressed in colitis and they are regulated by CEBPB through two super-enhancers, and we further demonstrate their role in vivo and in vitro. Nintedanib may be a potential treatment for IBD. Super-enhancers may be a new way to explore the pathogenesis of colitis.

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The role of phosphoenolpyruvate carboxykinase in neuronal steroidogenesis under acute inflammation

Cited by 15 publications

References 20 publications

Reciprocal Changes in Phosphoenolpyruvate Carboxykinase and Pyruvate Kinase with Age Are a Determinant of Aging in Caenorhabditis elegans

Reciprocal Changes in Phosphoenolpyruvate Carboxykinase and Pyruvate Kinase with Age Are a Determinant of Aging in Caenorhabditis elegans

Reprogramming of energy metabolism as a driver of aging

Nintedanib Alleviates Experimental Colitis by Inhibiting CEBPB/PCK1 and CEBPB/EFNA1 Pathways

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