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Open AccessArticle

Proteome Characteristics of Non-Alcoholic Steatohepatitis Liver Tissue and Associated Hepatocellular Carcinomas

by Anna Kakehashi, Vasily E. Stefanov, Naomi Ishii, Takahiro Okuno, Hideki Fujii, Kazuaki Kawai, Norifumi Kawada and Hideki Wanibuchi

Int. J. Mol. Sci. 2017, 18(2), 434; https://doi.org/10.3390/ijms18020434 - 17 Feb 2017

Cited by 22 | Viewed by 6939

Abstract

To uncover mechanisms of nonalcoholic steatohepatitis (NASH) associated hepatocarcinogenesis, we compared the proteomes of human NASH-associated liver biopsies, resected hepatocellular carcinomas (HCCs) and HCCs of HCV⁺ patients with normal liver tissue of patients with gastrointestinal tumor metastasis, in formalin-fixed paraffin-embedded samples obtained [...] Read more.

To uncover mechanisms of nonalcoholic steatohepatitis (NASH) associated hepatocarcinogenesis, we compared the proteomes of human NASH-associated liver biopsies, resected hepatocellular carcinomas (HCCs) and HCCs of HCV⁺ patients with normal liver tissue of patients with gastrointestinal tumor metastasis, in formalin-fixed paraffin-embedded samples obtained after surgery in our hospital during the period from 2006 to 2011. In addition, proteome analysis of liver tumors in male STAM NASH-model mice was performed. Similar changes in the proteome spectrum such as overexpression of enzymes involved in lipid, cholesterol and bile acid biosynthesis and examples associated with suppression of fatty acid oxidation and catabolism, alcohol metabolism, mitochondrial function as well as low expression levels of cytokeratins 8 and 18 were observed in both human NASH biopsies and NASH HCCs, but not HCV⁺ HCCs. Alterations in downstream protein expression pointed to significant activation of transforming growth factor β, SMAD family member 3, β-catenin, Nrf2, SREBP-LXRα and nuclear receptor-interacting protein 1 (NRIP1), and inhibition of PPARs and p53 in human NASH biopsies and/or HCCs, suggesting their involvement in accumulation of lipids, development of fibrosis, oxidative stress, cell proliferation and suppression of apoptosis in NASH hepatocarcinogenesis. In STAM mice, PPARs inhibition was not obvious, while expression of cytokeratins 8 and 18 was elevated, indicative of essential differences between human and mouse NASH pathogenesis. Full article

(This article belongs to the Special Issue Linking Nutrition and Energy Metabolism: Roles of PPARs in Healthy and in Disrupted Metabolic Homeostasis)

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4529 KiB

Open AccessArticle

Hepatic Fasting-Induced PPARα Activity Does Not Depend on Essential Fatty Acids

by Arnaud Polizzi, Edwin Fouché, Simon Ducheix, Frédéric Lasserre, Alice P. Marmugi, Laila Mselli-Lakhal, Nicolas Loiseau, Walter Wahli, Hervé Guillou and Alexandra Montagner

Int. J. Mol. Sci. 2016, 17(10), 1624; https://doi.org/10.3390/ijms17101624 - 24 Sep 2016

Cited by 7 | Viewed by 4978

Abstract

The liver plays a central role in the regulation of fatty acid metabolism, which is highly sensitive to transcriptional responses to nutrients and hormones. Transcription factors involved in this process include nuclear hormone receptors. One such receptor, PPARα, which is highly expressed in [...] Read more.

The liver plays a central role in the regulation of fatty acid metabolism, which is highly sensitive to transcriptional responses to nutrients and hormones. Transcription factors involved in this process include nuclear hormone receptors. One such receptor, PPARα, which is highly expressed in the liver and activated by a variety of fatty acids, is a critical regulator of hepatic fatty acid catabolism during fasting. The present study compared the influence of dietary fatty acids and fasting on hepatic PPARα-dependent responses. Pparα^−/− male mice and their wild-type controls were fed diets containing different fatty acids for 10 weeks prior to being subjected to fasting or normal feeding. In line with the role of PPARα in sensing dietary fatty acids, changes in chronic dietary fat consumption influenced liver damage during fasting. The changes were particularly marked in mice fed diets lacking essential fatty acids. However, fasting, rather than specific dietary fatty acids, induced acute PPARα activity in the liver. Taken together, the data imply that the potent signalling involved in triggering PPARα activity during fasting does not rely on essential fatty acid-derived ligand. Full article

(This article belongs to the Special Issue Linking Nutrition and Energy Metabolism: Roles of PPARs in Healthy and in Disrupted Metabolic Homeostasis)

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7219 KiB

Open AccessArticle

Sex-Based Selectivity of PPARγ Regulation in Th1, Th2, and Th17 Differentiation

by Hong-Jai Park, Hyeon-Soo Park, Jae-Ung Lee, Alfred L. M. Bothwell and Je-Min Choi

Int. J. Mol. Sci. 2016, 17(8), 1347; https://doi.org/10.3390/ijms17081347 - 18 Aug 2016

Cited by 36 | Viewed by 7301

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) has recently been recognized to regulate adaptive immunity through Th17 differentiation, Treg functions, and T_FH responses. However, its role in adaptive immunity and autoimmune disease is still not clear, possibly due to sexual differences. Here, we investigated [...] Read more.

Peroxisome proliferator-activated receptor gamma (PPARγ) has recently been recognized to regulate adaptive immunity through Th17 differentiation, Treg functions, and T_FH responses. However, its role in adaptive immunity and autoimmune disease is still not clear, possibly due to sexual differences. Here, we investigated in vitro treatment study with the PPARγ agonist pioglitazone to compare Th1, Th2, and Th17 differentiation in male and female mouse splenic T cells. Pioglitazone treatment significantly inhibited various effector T cell differentiations including Th1, Th2, and Th17 cells from female naïve T cells, but it selectively reduced IL-17 production in male Th17 differentiation. Interestingly, pioglitazone and estradiol (E2) co-treatment of T cells in males inhibited differentiation of Th1, Th2, and Th17 cells, suggesting a mechanism for the greater sensitivity of PPARγ to ligand treatment in the regulation of effector T cell differentiation in females. Collectively, these results demonstrate that PPARγ selectively inhibits Th17 differentiation only in male T cells and modulates Th1, Th2, and Th17 differentiation in female T cells based on different level of estrogen exposure. Accordingly, PPARγ could be an important immune regulator of sexual differences in adaptive immunity. Full article

(This article belongs to the Special Issue Linking Nutrition and Energy Metabolism: Roles of PPARs in Healthy and in Disrupted Metabolic Homeostasis)

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1936 KiB

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The Effect of Resveratrol and Quercetin Treatment on PPAR Mediated Uncoupling Protein (UCP-) 1, 2, and 3 Expression in Visceral White Adipose Tissue from Metabolic Syndrome Rats

by Vicente Castrejón-Tellez, José Manuel Rodríguez-Pérez, Israel Pérez-Torres, Nonanzit Pérez-Hernández, Alfredo Cruz-Lagunas, Verónica Guarner-Lans, Gilberto Vargas-Alarcón and María Esther Rubio-Ruiz

Int. J. Mol. Sci. 2016, 17(7), 1069; https://doi.org/10.3390/ijms17071069 - 5 Jul 2016

Cited by 43 | Viewed by 6645

Abstract

Uncoupling proteins (UCPs) are members of the mitochondrial anion carrier superfamily involved in the control of body temperature and energy balance regulation. They are currently proposed as therapeutic targets for treating obesity and metabolic syndrome (MetS). We studied the gene expression regulation of [...] Read more.

Uncoupling proteins (UCPs) are members of the mitochondrial anion carrier superfamily involved in the control of body temperature and energy balance regulation. They are currently proposed as therapeutic targets for treating obesity and metabolic syndrome (MetS). We studied the gene expression regulation of UCP1, -2, and -3 in abdominal white adipose tissue (WAT) from control and MetS rats treated with two doses of a commercial mixture of resveratrol (RSV) and quercetin (QRC). We found that UCP2 was the predominantly expressed isoform, UCP3 was present at very low levels, and UCP1 was undetectable. The treatment with RSV + QRC did not modify UCP3 levels; however, it significantly increased UCP2 mRNA in control and MetS rats in association with an increase in oleic and linoleic fatty acids. WAT from MetS rats showed a significantly increased expression of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ when compared to the control group. Furthermore, PPAR-α protein levels were increased by the highest dose of RSV + QRC in the control and MetS groups. PPAR-γ expression was only increased in the control group. We conclude that the RSV + QRC treatment leads to overexpression of UCP2, which is associated with an increase in MUFA and PUFA, which might increase PPAR-α expression. Full article

(This article belongs to the Special Issue Linking Nutrition and Energy Metabolism: Roles of PPARs in Healthy and in Disrupted Metabolic Homeostasis)

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Review

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Open AccessReview

Regulation of Ketone Body Metabolism and the Role of PPARα

by Maja Grabacka, Malgorzata Pierzchalska, Matthew Dean and Krzysztof Reiss

Int. J. Mol. Sci. 2016, 17(12), 2093; https://doi.org/10.3390/ijms17122093 - 13 Dec 2016

Cited by 233 | Viewed by 34556

Abstract

Ketogenesis and ketolysis are central metabolic processes activated during the response to fasting. Ketogenesis is regulated in multiple stages, and a nuclear receptor peroxisome proliferator activated receptor α (PPARα) is one of the key transcription factors taking part in this regulation. PPARα is [...] Read more.

Ketogenesis and ketolysis are central metabolic processes activated during the response to fasting. Ketogenesis is regulated in multiple stages, and a nuclear receptor peroxisome proliferator activated receptor α (PPARα) is one of the key transcription factors taking part in this regulation. PPARα is an important element in the metabolic network, where it participates in signaling driven by the main nutrient sensors, such as AMP-activated protein kinase (AMPK), PPARγ coactivator 1α (PGC-1α), and mammalian (mechanistic) target of rapamycin (mTOR) and induces hormonal mediators, such as fibroblast growth factor 21 (FGF21). This work describes the regulation of ketogenesis and ketolysis in normal and malignant cells and briefly summarizes the positive effects of ketone bodies in various neuropathologic conditions. Full article

(This article belongs to the Special Issue Linking Nutrition and Energy Metabolism: Roles of PPARs in Healthy and in Disrupted Metabolic Homeostasis)

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2765 KiB

Open AccessReview

Is the Mouse a Good Model of Human PPARγ-Related Metabolic Diseases?

by Attila Pap, Ixchelt Cuaranta-Monroy, Matthew Peloquin and Laszlo Nagy

Int. J. Mol. Sci. 2016, 17(8), 1236; https://doi.org/10.3390/ijms17081236 - 30 Jul 2016

Cited by 17 | Viewed by 9208

Abstract

With the increasing number of patients affected with metabolic diseases such as type 2 diabetes, obesity, atherosclerosis and insulin resistance, academic researchers and pharmaceutical companies are eager to better understand metabolic syndrome and develop new drugs for its treatment. Many studies have focused [...] Read more.

With the increasing number of patients affected with metabolic diseases such as type 2 diabetes, obesity, atherosclerosis and insulin resistance, academic researchers and pharmaceutical companies are eager to better understand metabolic syndrome and develop new drugs for its treatment. Many studies have focused on the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ), which plays a crucial role in adipogenesis and lipid metabolism. These studies have been able to connect this transcription factor to several human metabolic diseases. Due to obvious limitations concerning experimentation in humans, animal models—mainly mouse models—have been generated to investigate the role of PPARγ in different tissues. This review focuses on the metabolic features of human and mouse PPARγ-related diseases and the utility of the mouse as a model. Full article

(This article belongs to the Special Issue Linking Nutrition and Energy Metabolism: Roles of PPARs in Healthy and in Disrupted Metabolic Homeostasis)

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Open AccessReview

Modulation of PPAR Expression and Activity in Response to Polyphenolic Compounds in High Fat Diets

by J. Abraham Domínguez-Avila, Gustavo A. González-Aguilar, Emilio Alvarez-Parrilla and Laura A. De la Rosa

Int. J. Mol. Sci. 2016, 17(7), 1002; https://doi.org/10.3390/ijms17071002 - 29 Jun 2016

Cited by 59 | Viewed by 7251

Abstract

Peroxisome proliferator-activated receptors (PPAR) are transcription factors that modulate energy metabolism in liver, adipose tissue and muscle. High fat diets (HFD) can negatively impact PPAR expression or activity, favoring obesity, dyslipidemia, insulin resistance and other conditions. However, polyphenols (PP) found in vegetable foodstuffs [...] Read more.

Peroxisome proliferator-activated receptors (PPAR) are transcription factors that modulate energy metabolism in liver, adipose tissue and muscle. High fat diets (HFD) can negatively impact PPAR expression or activity, favoring obesity, dyslipidemia, insulin resistance and other conditions. However, polyphenols (PP) found in vegetable foodstuffs are capable of positively modulating this pathway. We therefore focused this review on the possible effects that PP can have on PPAR when administered together with HFD. We found that PP from diverse sources, such as coffee, olives, rice, berries and others, are capable of inducing the expression of genes involved in a decrease of adipose mass, liver and serum lipids and lipid biosynthesis in animal and cell models of HFD. Since cells or gut bacteria can transform PP into different metabolites, it is possible that a synergistic or antagonistic effect ultimately occurs. PP molecules from vegetable sources are an interesting option to maintain or return to a state of energy homeostasis, possibly due to an adequate PPAR expression and activity. Full article

(This article belongs to the Special Issue Linking Nutrition and Energy Metabolism: Roles of PPARs in Healthy and in Disrupted Metabolic Homeostasis)

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Open AccessReview

Pleiotropic Actions of Peroxisome Proliferator-Activated Receptors (PPARs) in Dysregulated Metabolic Homeostasis, Inflammation and Cancer: Current Evidence and Future Perspectives

by Antonio Simone Laganà, Salvatore Giovanni Vitale, Angela Nigro, Vincenza Sofo, Francesca Maria Salmeri, Paola Rossetti, Agnese Maria Chiara Rapisarda, Sandro La Vignera, Rosita Angela Condorelli, Gianluca Rizzo and Massimo Buscema

Int. J. Mol. Sci. 2016, 17(7), 999; https://doi.org/10.3390/ijms17070999 - 24 Jun 2016

Cited by 127 | Viewed by 8302

Abstract

Background: Peroxisome proliferator-activated receptors (PPARs) have demonstrated a lot of important effects in the regulation of glucose and lipid metabolism and in the correct functioning of adipose tissue. Recently, many studies have evaluated a possible effect of PPARs on tumor cells. The [...] Read more.

Background: Peroxisome proliferator-activated receptors (PPARs) have demonstrated a lot of important effects in the regulation of glucose and lipid metabolism and in the correct functioning of adipose tissue. Recently, many studies have evaluated a possible effect of PPARs on tumor cells. The purpose of this review is to describe the effects of PPARs, their action and their future prospective; Methods: Narrative review aimed to synthesize cutting-edge evidence retrieved from searches of computerized databases; Results: PPARs play a key role in metabolic diseases, which include several cardiovascular diseases, insulin resistance, type 2 diabetes, metabolic syndrome, impaired immunity and the increasing risk of cancer; in particular, PPARα and PPARβ/δ mainly enable energy combustion, while PPARγ contributes to energy storage by enhancing adipogenesis; Conclusion: PPAR agonists could represent interesting types of molecules that can treat not only metabolic diseases, but also inflammation and cancer. Additional research is needed for the identification of high-affinity, high-specificity agonists for the treatment of obesity, type 2 diabetes (T2DM) and other metabolic diseases. Further studies are needed also to elucidate the role of PPARs in cancer. Full article

(This article belongs to the Special Issue Linking Nutrition and Energy Metabolism: Roles of PPARs in Healthy and in Disrupted Metabolic Homeostasis)

651 KiB

Open AccessReview

PPARs Link Early Life Nutritional Insults to Later Programmed Hypertension and Metabolic Syndrome

by You-Lin Tain, Chien-Ning Hsu and Julie Y. H. Chan

Int. J. Mol. Sci. 2016, 17(1), 20; https://doi.org/10.3390/ijms17010020 - 24 Dec 2015

Cited by 62 | Viewed by 6695

Abstract

Hypertension is an important component of metabolic syndrome. Adulthood hypertension and metabolic syndrome can be programmed in response to nutritional insults in early life. Peroxisome proliferator-activated receptors (PPARs) serve as a nutrient-sensing signaling linking nutritional programming to hypertension and metabolic syndrome. All three [...] Read more.

Hypertension is an important component of metabolic syndrome. Adulthood hypertension and metabolic syndrome can be programmed in response to nutritional insults in early life. Peroxisome proliferator-activated receptors (PPARs) serve as a nutrient-sensing signaling linking nutritional programming to hypertension and metabolic syndrome. All three members of PPARs, PPARα, PPARβ/δ, and PPARγ, are expressed in the kidney and involved in blood pressure control. This review provides an overview of potential clinical applications of targeting on the PPARs in the kidney to prevent programmed hypertension and metabolic syndrome, with an emphasis on the following areas: mechanistic insights to interpret programmed hypertension; the link between the PPARs, nutritional insults, and programmed hypertension and metabolic syndrome; the impact of PPAR signaling pathway in a maternal high-fructose model; and current experimental studies on early intervention by PPAR modulators to prevent programmed hypertension and metabolic syndrome. Animal studies employing a reprogramming strategy via targeting PPARs to prevent hypertension have demonstrated interesting results. It is critical that the observed effects on developmental reprogramming in animal models are replicated in human studies, to halt the globally-growing epidemic of metabolic syndrome-related diseases. Full article

(This article belongs to the Special Issue Linking Nutrition and Energy Metabolism: Roles of PPARs in Healthy and in Disrupted Metabolic Homeostasis)

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