PPAR-α as a Key Nutritional and Environmental Sensor for Metabolic Adaptation

Contreras, Alejandra; Torres, Nimbe; Tovar, Armando R.

doi:10.3945/an.113.003798

Cited by 190 publications

(162 citation statements)

References 130 publications

(152 reference statements)

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“…It is known that PPARa functions as a lipid sensor in the liver and recognizes and responds to the influx of fatty acids by stimulating the transcription of specific genes related to lipid metabolism (Contreras et al 2013). Also, there is evidence that Ppara-null mice develop lipid steatosis (Costet et al 1998) due to decreased capacity to oxidize fatty acids.…”

Section: Resultsmentioning

confidence: 98%

PPARα via HNF4α regulates the expression of genes encoding hepatic amino acid catabolizing enzymes to maintain metabolic homeostasis

et al. 2015

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The liver is the main organ involved in the metabolism of amino acids (AA), which are oxidized by amino acid catabolizing enzymes (AACE). Peroxisome proliferator-activated receptor-α (PPARα) stimulates fatty acid β-oxidation, and there is evidence that it can modulate hepatic AA oxidation during the transition of energy fuels. To understand the role and mechanism of PPARα's regulation of AA catabolism, the metabolic and molecular adaptations of Ppara-null mice were studied. The role of PPARα on AA metabolism was examined by in vitro and in vivo studies. In wild-type and Ppara-null mice, fed increasing concentrations of the dietary protein/carbohydrate ratio, we measured metabolic parameters, and livers were analyzed by microarray analysis, histology and Western blot. Functional enrichment analysis, EMSA and gene reporter assays were performed. Ppara-null mice presented increased expression of AACE in liver affecting AA, lipid and carbohydrate metabolism. Ppara-null mice had increased glucagon/insulin ratio (7.2-fold), higher serum urea (73.1 %), lower body protein content (19.7 %) and decreased several serum AA in response to a high-protein/low-carbohydrate diet. A functional network of differentially expressed genes, suggested that changes in the expression of AACE were regulated by an interrelationship between PPARα and HNF4α. Our data indicated that the expression of AACE is down-regulated through PPARα by attenuating HNF4α transcriptional activity as observed in the serine dehydratase gene promoter. PPARα via HNF4α maintains body protein metabolic homeostasis by down-regulating genes involved in amino acid catabolism for preserving body nitrogen.

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Section: Resultsmentioning

confidence: 98%

PPARα via HNF4α regulates the expression of genes encoding hepatic amino acid catabolizing enzymes to maintain metabolic homeostasis

et al. 2015

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“…PPARα is activated by energy deprivation, fasting, and fibrate agents. It is expressed primarily in the liver, heart, kidney and intestine [7,8]. Transcriptional regulation is achieved by the binding of PPAR/retinoid X receptor heterodimers to PPAR response elements (PPREs) in target gene promoters [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of cereblon by fenofibrate ameliorates alcoholic liver disease by enhancing AMPK

Kim

Lee

Hwang

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Alcohol consumption exacerbates alcoholic liver disease by attenuating the activity of AMP-activated protein kinase (AMPK). AMPK is activated by fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, and inhibited by direct interaction with cereblon (CRBN), a component of an E3 ubiquitin ligase complex. Based on these preliminary findings, we investigated that CRBN would be up-regulated in the liver by alcohol consumption and that CRBN deficiency would ameliorate hepatic steatosis and pro-inflammatory responses in alcohol-fed mice by increasing AMPK activity. Wild-type, CRBN and PPARα null mice were fed an alcohol-containing liquid diet and administered with fenofibrate. Gene expression profiles and metabolic changes were measured in the liver and blood of these mice. Expression of CRBN, cytochrome P450 2E1 (CYP2E1), lipogenic genes, pro-inflammatory cytokines, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were increased in the Lieber-DeCarli alcohol-challenged mice. Fenofibrate attenuated the induction of CRBN and reduced hepatic steatosis and pro-inflammatory markers in these mice. Ablation of the gene encoding CRBN produced the same effect as fenofibrate. The increase in CRBN gene expression by alcohol and the reduction of CRBN expression by fenofibrate were negated in PPARα null mice. Fenofibrate increased the recruitment of PPARα on CRBN gene promoter in WT mice but not in PPARα null mice. Silencing of AMPK prevented the beneficial effects of fenofibrate. These results demonstrate that activation of PPARα by fenofibrate alleviates alcohol-induced hepatic steatosis and inflammation by reducing the inhibition of AMPK by CRBN. CRBN is a potential therapeutic target for the alcoholic liver disease.

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“…In this study, alcohol treatment increased CRBN gene expression by suppressing the PPARα-dependent pathway, suggesting that PPARα is a negative transcriptional regulator of CRBN. PPARα is an important lipid sensor in the liver that responds to different metabolic conditions [12], which could explain why CRBN responds to metabolic conditions and regulates AMPK activity. An early study of CRBN demonstrated that hypoxia/ reoxygenation (H/R) and ROS stimulation enhance mRNA and protein expression of CRBN in neuroblastoma cells [42].…”

Section: Potential Regulators Of Crbn Expressionmentioning

confidence: 99%

Cereblon in health and disease

Kim

Nyamaa

et al. 2016

Pflugers Arch - Eur J Physiol

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Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that has been linked to autosomal recessive non-syndromic mental retardation. Several key findings suggest diverse roles of CRBN, including its regulation of the large-conductance calcium- and voltage-activated potassium (BKCa) channels, regulation of thalidomide-binding proteins, and mediation of lenalidomide treatment in multiple myeloma. Recent studies also indicate that CRBN is involved in energy metabolism and negatively regulates AMP-activated protein kinase signaling. Mice with genetic depletion of CRBN are resistant to various stress conditions including a high-fat diet, endoplasmic reticulum stress, ischemia/reperfusion injury, and alcohol-related liver damage. In this review, we discuss the various roles of CRBN in human health and disease and suggest avenues for further research to enhance our basic knowledge and clinical application of CRBN.

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PPAR-α as a Key Nutritional and Environmental Sensor for Metabolic Adaptation

Cited by 190 publications

References 130 publications

PPARα via HNF4α regulates the expression of genes encoding hepatic amino acid catabolizing enzymes to maintain metabolic homeostasis

PPARα via HNF4α regulates the expression of genes encoding hepatic amino acid catabolizing enzymes to maintain metabolic homeostasis

Inhibition of cereblon by fenofibrate ameliorates alcoholic liver disease by enhancing AMPK

Cereblon in health and disease

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