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Journal ArticleDOI

The role and regulation of the peroxisome proliferator activated receptor alpha in human liver.

01 May 2017-Biochimie (Biochimie)-Vol. 136, pp 75-84
TL;DR: In addition to helping to correct dyslipidemia, PPARα agonists may hold promise as a therapy for patients with cholestatic liver diseases, non-alcoholic fatty liver disease, and/or type 2 diabetes.
About: This article is published in Biochimie.The article was published on 2017-05-01. It has received 237 citations till now. The article focuses on the topics: Peroxisome proliferator-activated receptor alpha & Steatohepatitis.
Citations
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Journal ArticleDOI
TL;DR: This narrative review investigates the molecular mechanisms of hepatic steatosis in NAFLD, focusing on the four major pathways contributing to lipid homeostasis in the liver.
Abstract: Non-alcoholic fatty liver disease (NAFLD) is currently the world’s most common liver disease, estimated to affect up to one-fourth of the population. Hallmarked by hepatic steatosis, NAFLD is associated with a multitude of detrimental effects and increased mortality. This narrative review investigates the molecular mechanisms of hepatic steatosis in NAFLD, focusing on the four major pathways contributing to lipid homeostasis in the liver. Hepatic steatosis is a consequence of lipid acquisition exceeding lipid disposal, i.e., the uptake of fatty acids and de novo lipogenesis surpassing fatty acid oxidation and export. In NAFLD, hepatic uptake and de novo lipogenesis are increased, while a compensatory enhancement of fatty acid oxidation is insufficient in normalizing lipid levels and may even promote cellular damage and disease progression by inducing oxidative stress, especially with compromised mitochondrial function and increased oxidation in peroxisomes and cytochromes. While lipid export initially increases, it plateaus and may even decrease with disease progression, sustaining the accumulation of lipids. Fueled by lipo-apoptosis, hepatic steatosis leads to systemic metabolic disarray that adversely affects multiple organs, placing abnormal lipid metabolism associated with NAFLD in close relation to many of the current life-style-related diseases.

646 citations


Cites background from "The role and regulation of the pero..."

  • ...Activation of PPARα induces the transcription of a range of genes related to FAO in the mitochondria, peroxisomes, and cytochromes, thereby reducing hepatic lipid levels [77, 80, 81, 83]....

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Journal ArticleDOI
TL;DR: The CONTAM Panel concluded that parts of the European population exceed this tolerable weekly intake (TWI) of 4.4 ng/kg bw per week, which is of concern, and protects against other potential adverse effects observed in humans.
Abstract: The European Commission asked EFSA for a scientific evaluation on the risks to human health related to the presence of perfluoroalkyl substances (PFASs) in food. Based on several similar effects in animals, toxicokinetics and observed concentrations in human blood, the CONTAM Panel decided to perform the assessment for the sum of four PFASs: PFOA, PFNA, PFHxS and PFOS. These made up half of the lower bound (LB) exposure to those PFASs with available occurrence data, the remaining contribution being primarily from PFASs with short half‐lives. Equal potencies were assumed for the four PFASs included in the assessment. The mean LB exposure in adolescents and adult age groups ranged from 3 to 22, the 95th percentile from 9 to 70 ng/kg body weight (bw) per week. Toddlers and ‘other children’ showed a twofold higher exposure. Upper bound exposure was 4‐ to 49‐fold higher than LB levels, but the latter were considered more reliable. ‘Fish meat’, ‘Fruit and fruit products’ and ‘Eggs and egg products’ contributed most to the exposure. Based on available studies in animals and humans, effects on the immune system were considered the most critical for the risk assessment. From a human study, a lowest BMDL 10 of 17.5 ng/mL for the sum of the four PFASs in serum was identified for 1‐year‐old children. Using PBPK modelling, this serum level of 17.5 ng/mL in children was estimated to correspond to long‐term maternal exposure of 0.63 ng/kg bw per day. Since accumulation over time is important, a tolerable weekly intake (TWI) of 4.4 ng/kg bw per week was established. This TWI also protects against other potential adverse effects observed in humans. Based on the estimated LB exposure, but also reported serum levels, the CONTAM Panel concluded that parts of the European population exceed this TWI, which is of concern.

357 citations

Journal ArticleDOI
TL;DR: The full potential of this nuclear receptor subtype as a versatile drug target with high plasticity becomes increasingly clear, and a novel generation of agonists may pave the way for novel fields of applications.
Abstract: Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor of clinical interest as a drug target in various metabolic disorders PPARα also exhibits marked anti-inflammatory capacities The first-generation PPARα agonists, the fibrates, have however been hampered by drug-drug interaction issues, statin drop-in, and ill-designed cardiovascular intervention trials Notwithstanding, understanding the molecular mechanisms by which PPARα works will enable control of its activities as a drug target for metabolic diseases with an underlying inflammatory component Given its role in reshaping the immune system, the full potential of this nuclear receptor subtype as a versatile drug target with high plasticity becomes increasingly clear, and a novel generation of agonists may pave the way for novel fields of applications

342 citations

Journal ArticleDOI
TL;DR: For PFOS, the increase in serum total cholesterol in adults, and the decrease in antibody response at vaccination in children were identified as the critical effects and the CONTAM Panel established a tolerable weekly intake (TWI) of 13 ng/kg body weight (bw) per week for PFOS and 6 ng/ kg bw for PFOA.
Abstract: Acknowledgements: The Panel wishes to thank the hearing experts: Tony Fletcher, Philippe Adam Grandjean and Marco Zeilmaker, and EFSA staff members: Davide Arcella for the support provided to this scientific output. The Panel acknowledges all European Competent Authorities that provided occurrence data on perfluoroalkylated substances in food, and supported the data collection for the Comprehensive European Food Consumption Database. The Panel would also like to thank the following authors and co‐authors for providing additional data in relation to their respective studies: Esben Budtz‐Jorgensen, Jerry Campbell, Jessie A Gleason, Berit Granum, Mette Sorenson, Kyle Steenland and Kristina W Whitworth.

316 citations


Cites background from "The role and regulation of the pero..."

  • ...Due to lack in liver biopsies, products of PPARa target genes were determined in patients’ sera and elevated protein levels of APOA2, ANGPTL4 and FGF21, confirmed that PPARa agonists are able to activate effectively this receptor in human liver (Kersten and Stienstra, 2017)....

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Journal ArticleDOI
TL;DR: This Review describes the pathophysiological roles of peroxisome proliferator-activated receptors (PPARs) in nonalcoholic steatohepatitis and related metabolic diseases, and summarizes the preclinical and clinical data on the use of PPAR agonists to treat nonalcoholIC steato hepatitis as part of a systemic metabolic disease.
Abstract: The increasing epidemic of obesity worldwide is linked to serious health effects, including increased prevalence of type 2 diabetes mellitus, cardiovascular disease and nonalcoholic fatty liver disease (NAFLD). NAFLD is the liver manifestation of the metabolic syndrome and includes the spectrum of liver steatosis (known as nonalcoholic fatty liver) and steatohepatitis (known as nonalcoholic steatohepatitis), which can evolve into progressive liver fibrosis and eventually cause cirrhosis. Although NAFLD is becoming the number one cause of chronic liver diseases, it is part of a systemic disease that affects many other parts of the body, including adipose tissue, pancreatic β-cells and the cardiovascular system. The pathomechanism of NAFLD is multifactorial across a spectrum of metabolic derangements and changes in the host microbiome that trigger low-grade inflammation in the liver and other organs. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear regulatory factors that provide fine tuning for key elements of glucose and fat metabolism and regulate inflammatory cell activation and fibrotic processes. This Review summarizes and discusses the current literature on NAFLD as the liver manifestation of the systemic metabolic syndrome and focuses on the role of PPARs in the pathomechanisms as well as in the potential targeting of disease.

142 citations

References
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Journal ArticleDOI
15 Dec 1995-Cell
TL;DR: This research presents a new probabilistic procedure called ‘spot-spot analysis’ to characterize the response of the immune system to the presence of E.coli.

6,818 citations

Journal ArticleDOI
18 Oct 1990-Nature
TL;DR: A member of the steroid hormone receptor superfamily of ligand-activated transcription factors is cloned that is activated by a diverse class of rodent hepatocarcinogens that causes proliferation of peroxisomes.
Abstract: We have cloned a member of the steroid hormone receptor superfamily of ligand-activated transcription factors. The receptor homologue is activated by a diverse class of rodent hepatocarcinogens that causes proliferation of peroxisomes. Identification of a peroxisome proliferator-activated receptor should help elucidate the mechanism of the hypolipidaemic effect of these hepatocarcinogens and aid evaluation of their potential carcinogenic risk to man.

3,370 citations

Journal ArticleDOI
TL;DR: This work has shown that direct expression of PPAR mRNAs in the absence of a specific carrier gene results in down-regulation in the activity of other PPARs, and these properties are consistent with those of a “spatially aggregating substance”.
Abstract: I. Introduction II. Molecular Aspects A. PPAR isotypes: identity, genomic organization and chromosomal localization B. DNA binding properties C. PPAR ligand-binding properties D. Alternative pathways for PPAR activation E. PPAR-mediated transactivation properties III. Physiological Aspects A. Differential expression of PPAR mRNAs B. PPAR target genes and functions in fatty acid metabolism C. PPARs and control of inflammatory responses D. PPARs and atherosclerosis E. PPARs and the development of the fetal epidermal permeability barrier F. PPARs, carcinogenesis, and control of the cell cycle IV. Conclusions

3,028 citations

Journal ArticleDOI
TL;DR: It is shown here that specific FAs, eicosanoids, and hypolipidemic drugs are ligands for PPARα or PPARδ, and a novel conformation-based assay is developed that screens activators for their ability to bind to PPAR α/δ and induce DNA binding.
Abstract: Fatty acids (FAs) and their derivatives are essential cellular metabolites whose concentrations must be closely regulated. This implies that regulatory circuits exist which can sense changes in FA levels. Indeed, the peroxisome proliferator-activated receptor α (PPARα) regulates lipid homeostasis and is transcriptionally activated by a variety of lipid-like compounds. It remains unclear as to how these structurally diverse compounds can activate a single receptor. We have developed a novel conformation-based assay that screens activators for their ability to bind to PPARα/δ and induce DNA binding. We show here that specific FAs, eicosanoids, and hypolipidemic drugs are ligands for PPARα or PPARδ. Because altered FA levels are associated with obesity, atherosclerosis, hypertension, and diabetes, PPARs may serve as molecular sensors that are central to the development and treatment of these metabolic disorders.

2,066 citations

Journal ArticleDOI
TL;DR: Evidence that PPARs serve as physiological sensors of lipid levels is provided and a molecular mechanism whereby dietary fatty acids can modulate lipid homeostasis is suggested.
Abstract: Peroxisome proliferator-activated receptors (PPARs) alpha and gamma are key regulators of lipid homeostasis and are activated by a structurally diverse group of compounds including fatty acids, eicosanoids, and hypolipidemic drugs such as fibrates and thiazolidinediones. While thiazolidinediones and 15-deoxy-Delta12, 14-prostaglandin J2 have been shown to bind to PPARgamma, it has remained unclear whether other activators mediate their effects through direct interactions with the PPARs or via indirect mechanisms. Here, we describe a novel fibrate, designated GW2331, that is a high-affinity ligand for both PPARalpha and PPARgamma. Using GW2331 as a radioligand in competition binding assays, we show that certain mono- and polyunsaturated fatty acids bind directly to PPARalpha and PPARgamma at physiological concentrations, and that the eicosanoids 8(S)-hydroxyeicosatetraenoic acid and 15-deoxy-Delta12,14-prostaglandin J2 can function as subtype-selective ligands for PPARalpha and PPARgamma, respectively. These data provide evidence that PPARs serve as physiological sensors of lipid levels and suggest a molecular mechanism whereby dietary fatty acids can modulate lipid homeostasis.

2,054 citations