Nuclear Receptors as Therapeutic Targets in Liver Disease: Are We There Yet?

Rudraiah, Swetha; Zhang, Xi; Wang, Li

doi:10.1146/annurev-pharmtox-010715-103209

Cited by 73 publications

(74 citation statements)

References 146 publications

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“…Nuclear receptors are a class of proteins that mediate the activity of hormones and have been implicated in various diseases, including HCC (Rudraiah et al, 2016). The small heterodimer partner (SHP) is a unique transcriptional repressor (Zhou et al, 2010) and has been implicated as a critical inhibitor of HCC progression (Zhang et al, 2011b) by regulating multiple pathways involved in tumor growth, including cell proliferation , apoptosis (Farhana et al, 2007;Zhang et al, 2010), and migration and invasion .…”

Section: Introductionmentioning

confidence: 99%

Pyruvate Dehydrogenase Kinase 4 Deficiency Results in Expedited Cellular Proliferation through E2F1-Mediated Increase of Cyclins

Choiniere

Wang

2016

Mol Pharmacol

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Hepatocellular carcinoma (HCC) is a common form of cancer with prevalence worldwide. There are many factors that lead to the development and progression of HCC. This study aimed to identify potential new tumor suppressors, examine their function as cell cycle modulators, and investigate their impact on the cyclin family of proteins and cyclin-dependent kinases (CDKs). In this study, the pyruvate dehydrogenase kinase (PDK)4 gene was shown to have potential tumor suppressor characteristics. PDK4 expression was significantly downregulated in human HCC. Pdk4 2/2 mouse liver exhibited a consistent increase in cell cycle regulator proteins, including cyclin D1, cyclin E1, cyclin A2, some associated CDKs, and transcription factor E2F1.PDK4-knockdown HCC cells also progressed faster through the cell cycle, which concurrently expressed high levels of cyclins and E2F1 as seen in the Pdk4 2/2 mice. Interestingly, the induced cyclin E1 and cyclin A2 caused by Pdk4 deficiency was repressed by arsenic treatment in mouse liver and in HCC cells. E2f1 deficiency in E2f1 2/2 mouse liver or knockdown E2F1 using small hairpin RNAs in HCC cells significantly decreased cyclin E1, cyclin A2, and E2F1 proteins. In contrast, inhibition of PDK4 activity in HCC cells increased cyclin E1, cyclin A2, and E2F1 proteins. These findings demonstrate that PDK4 is a critical regulator of hepatocyte proliferation via E2F1-mediated regulation of cyclins.

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Section: Introductionmentioning

confidence: 99%

Pyruvate Dehydrogenase Kinase 4 Deficiency Results in Expedited Cellular Proliferation through E2F1-Mediated Increase of Cyclins

Choiniere

Wang

2016

Mol Pharmacol

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“…Humans have a total of 48 nuclear receptors while mice have 49 1. These nuclear receptors can be categorized into seven different subfamilies and are classified as NR0 to NR6 (Table 1).…”

Section: The Nuclear Receptor Superfamilymentioning

confidence: 99%

“…Another class of nuclear receptors is known as enigmatic orphan receptors, which have identified ligands, but ligand‐dependent regulation has not been firmly established. Members of these orphan receptor class include constitutive androstane receptor (CAR), estrogen‐related receptor (α/β/γ), hepatocyte nuclear factor (HNFα/γ), liver‐related homolog 1 (LRH‐1), and RAR‐related orphan receptors (RORα/β/γ) 1, 2, 3, 4…”

Section: The Nuclear Receptor Superfamilymentioning

confidence: 99%

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Nuclear receptors and liver disease: Summary of the 2017 basic research symposium

Tran

Liu

Huang

et al. 2018

Hepatology Communications

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The nuclear receptor superfamily contains important transcriptional regulators that play pleiotropic roles in cell differentiation, development, proliferation, and metabolic processes to govern liver physiology and pathology. Many nuclear receptors are ligand‐activated transcription factors that regulate the expression of their target genes by modulating transcriptional activities and epigenetic changes. Additionally, the protein complex associated with nuclear receptors consists of a multitude of coregulators, corepressors, and noncoding RNAs. Therefore, acquiring new information on nuclear receptors may provide invaluable insight into novel therapies and shed light on new interventions to reduce the burden and incidence of liver diseases. (Hepatology Communications 2018;2:765‐777)

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“…The GR, a nuclear receptor, is abundantly expressed in hepatocytes and other liver cells [37] and plays diverse roles in many cellular functions including cell proliferation [38]. The GCs act either via modulation of GR-independent cell membrane components (involving GCs-physiochemical interactions with components of cell membrane), cell membrane-bound GR (involving a MAPK pathway) or cytoplasmic GR to initiate rapid non-genomic cell signaling events [39-41].…”

Section: The Impact Of Psychosocial Stress and Glucocorticoids On Bodmentioning

confidence: 99%

Psychosocial-Stress, Liver Regeneration and Weight Gain: a Conspicuous Pathophysiological Triad

Ishtiaq

Khan

Arshad

2018

Cell Physiol Biochem

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Psychosocial stress alters several physiological parameters resulting in multiple disorders, particularly compromising the immune system thereby provoking various diseases including liver disorders. However, the plausible underlying mechanisms remain elusive. Recent literature provides mechanistic evidences of detrimental effects of psychosocial stress on physiology of different body organs including liver. The data of stress-induced pathophysiological changes in liver functions and obesity were systematically collected from PubMed, ScienceDirect and the Web of Science Databases published in English. Stress and glucocorticoids (GCs) control food intake and energy expenditure through appetite stimulators neuropeptide Y (NYP) and agouti-related protein (AgRP) in hypothalamus. Principle effectors of the activated hypothalamic-pituitary-adrenal (HPA) axis in response to psychosocial stress are proopiomelanocortin (POMC)-derived adrenocorticotropic hormone (ACTH) and GCs. Stress-induced GCs hyper-secretion triggers glucocorticoid receptor (GR)-dependent transcriptional factor, nuclear factor kappa B (NFκB), which interferes TNFα-IL6 and keap1-Nrf2 pathways in liver regeneration and obesity through fine-tuning of TNFα, IL6 and Nrf2 signaling. In this review, it is contrived upon existing evidence to put forward a model whereby exposure to life-stress has a prominent impact over weight gain and can alter the regenerative mode of a damaged liver through Keap1-Nrf2 and TNFa-IL6 pathways.

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Nuclear Receptors as Therapeutic Targets in Liver Disease: Are We There Yet?

Cited by 73 publications

References 146 publications

Pyruvate Dehydrogenase Kinase 4 Deficiency Results in Expedited Cellular Proliferation through E2F1-Mediated Increase of Cyclins

Pyruvate Dehydrogenase Kinase 4 Deficiency Results in Expedited Cellular Proliferation through E2F1-Mediated Increase of Cyclins

Nuclear receptors and liver disease: Summary of the 2017 basic research symposium

Psychosocial-Stress, Liver Regeneration and Weight Gain: a Conspicuous Pathophysiological Triad

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