Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease

Dong, Bingning; Saha, Pradip Kumar; Huang, Wendong; Chen, Wenling; Abu-Elheiga, Lutfi; Wakil, Salih J.; Stevens, Robert; Ilkayeva, Olga; Newgard, Christopher B.; Chan, Lawrence; Moore, David D.

doi:10.1073/pnas.0909731106

Cited by 226 publications

(259 citation statements)

References 39 publications

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“…Hyperglycemia and dyslipidemia are the hallmarks of obesity-associated type 2 diabetes. Activation of CAR by the synthetic agonist TCPOBOP increased insulin sensitivity and ameliorated liver steatosis in both high fat diet (HFD)-and leptin deficiency-induced obesity [77,78] . Several studies have shown that pharmacological activation and the genetic gain-of-function of CAR leads to lower hepatic triglyceride levels, whereas loss of CAR causes basal accumulation of triglycerides in the liver [79] .…”

Section: Car In Energy Metabolismmentioning

confidence: 99%

Deciphering the roles of the constitutive androstane receptor in energy metabolism

et al. 2014

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The constitutive androstane receptor (CAR) is initially defined as a xenobiotic nuclear receptor that protects the liver from injury. Detoxification of damaging chemicals is achieved by CAR-mediated induction of drug-metabolizing enzymes and transporters. More recent research has implicated CAR in energy metabolism, suggesting a therapeutic potential for CAR in metabolic diseases, such as type 2 diabetes and obesity. A better understanding of the mechanisms by which CAR regulates energy metabolism will allow us to take advantage of its effectiveness while avoiding its side effects. This review summarizes the current progress on the regulation of CAR nuclear translocation, upstream modulators of CAR activity, and the crosstalk between CAR and other transcriptional factors, with the aim of elucidating how CAR regulates glucose and lipid metabolism.

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Section: Car In Energy Metabolismmentioning

confidence: 99%

Deciphering the roles of the constitutive androstane receptor in energy metabolism

et al. 2014

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“…8 The liquid diet was ordered from Bio-serv (Frenchtown, NJ, USA), and prepared and maintained as manufacturer's protocols. Because CAR À/À mice are more susceptible to diabetes, 6,7 the maltose in the original recipe was replaced with isocaloric liquid-diet powder. Ethanol concentration was increased gradually from 1 to 5% within 4 weeks.…”

Section: Methodsmentioning

confidence: 99%

“…CAR À/À Mice are More Susceptible to Ethanol-induced Fat Accumulation and Hepatocyte Apoptosis As CAR activation improves metabolism of lipid and glucose in diabetes mellitus, 6,7 we examined whether the CAR À/À mice would exhibit higher grade of steatosis than the wild-type mice by H&E staining and Oil-Red O staining. The long-term ethanol diet feeding caused minor fat accumulation in the wild-type mice (Figures 2a and b).…”

Section: Chronicmentioning

confidence: 99%

“…5 Recent studies also reported that CAR has a role in diabetes mellitus and metabolism of glucose and lipid. 6,7 On the other hand, several nuclear receptors, PPARa, PPARg, PPARd, RAR, and HNF4a, have been shown to be involved in alcohol-induced liver injury. [8][9][10][11][12] Considering the importance of CAR in P450 enzyme expression and metabolisms of glucose and lipids, we ask whether CAR has a role in modulating alcoholinduced liver injury.…”

mentioning

confidence: 99%

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The nuclear receptor CAR modulates alcohol-induced liver injury

Chen

Meng

Wang

et al. 2011

Laboratory Investigation

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The constitutive androstane receptor (CAR) is a member of the nuclear receptor superfamily and a sensor and detoxifier of both xenobiotics and endobiotics. Recent studies also show that CAR participates in metabolism of glucose and lipid, and has an important role in fatty liver disease and diabetes. In this study, we investigate the roles of CAR in chronic and acute alcohol-induced liver injuries. The results showed that absence of CAR in rodents led to significantly increased susceptibility to chronic alcohol-induced liver injury, which was accompanied with elevated hepatocyte apoptosis and fat accumulation. However, pre-activation of CAR by a CAR agonist, TCPOBOP, strongly enhanced the hepatic toxicity by both chronic and acute alcohol infusion in wild-type, but not in CAR À/À mice. Gene expression analyses indicated that CAR pre-activation and alcohol infusion synergistically decreased the expression of enzymes that metabolize the alcohol in liver. These results support a role of CAR in modulating alcoholic liver injury and imply a risk of synergistic liver toxicity induced by alcohol and CAR activation.

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“…Some clues have been gathered from targeted gene disruptions in mice that result in a lean phenotype: these include p70 S6 kinase, 21 estrogen-related receptor-a, 22 corepressor RIP140, 23 the liver X receptors (LXRs), 24 CIDEA 25 and, most recently, the constitutive androstane receptor. 26,27 A question yet to be answered is what functions do these molecules share in common that, in their absence, lead to a significant shift in the expression of UCP1 and production of thermogenically active brown adipocytes within typical WAT depots?…”

Section: Targetsmentioning

confidence: 99%

Positive and negative control of Ucp1 gene transcription and the role of β-adrenergic signaling networks

2010

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Adrenergic receptor signaling in adipocytes controls not only the hydrolysis of triglycerides as fuel for other organs but is also a driver of brown adipocyte thermogenesis and energy consumption. As the appearance of these mitochondria-rich, thermogenically active cells in 'white' adipocyte depots is correlated with resistance to overnutrition and glucose intolerance, the molecular basis of their genesis and metabolic activity needs to be understood. b-adrenergic receptors regulate the enzymatic machinery for lipolysis and fuel utilization. They also coordinately stimulate the transcription of genes that support the specific functions of white and brown adipocytes. They accomplish this through the activation of a network of signaling pathways that include cAMP-dependent protein kinase and members of the mitogen-activated protein kinase family. In brown adipocytes, these kinases control the transcription of nuclear factors such as peroxisome proliferator-activated receptor-g coactivator-1s, as well as other molecules discovered to respond to adrenergic signals, to increase mitochondrial biogenesis and uncoupling protein-1 (UCP1) expression. However, it is also important to understand the mechanisms that may actively repress these energy-wasting processes. Toward that end, we provide evidence for an important role for the nuclear receptor LXRa as a cAMP-and oxysterol-dependent transcriptional repressor of the Ucp1 gene. Adipocytes from LXRa-null mice have increased expression of most 'markers' of brown adipocytes, increased mitochondrial mass and uncoupled respiration. These studies reveal potential new targets and directions for controlling the relative levels of white versus brown adipocytes as a means of metabolic fuel utilization in the struggle against obesity and related metabolic diseases.

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Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease

Cited by 226 publications

References 39 publications

Deciphering the roles of the constitutive androstane receptor in energy metabolism

Deciphering the roles of the constitutive androstane receptor in energy metabolism

The nuclear receptor CAR modulates alcohol-induced liver injury

Positive and negative control of Ucp1 gene transcription and the role of β-adrenergic signaling networks

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