The Experts below are selected from a list of 5688 Experts worldwide ranked by ideXlab platform

David M. Wilhite - One of the best experts on this subject based on the ideXlab platform.

Bart Staels - One of the best experts on this subject based on the ideXlab platform.

  • PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD
    Nature Reviews Endocrinology, 2017
    Co-Authors: Barbara Gross, Michal Pawlak, Philippe Lefebvre, Bart Staels
    Abstract:

    Obesity might be combated by reducing fat storage in white adipose tissue (WAT), increasing energy expenditure through adaptive thermogenesis in brown adipose tissue (BAT) and/or the browning of WAT In mouse models the three peroxisome proliferator-activated receptor (PPAR) isotypes regulate adaptive thermogenesis in BAT via distinct mechanisms; PPARα and PPARγ ligands also promote WAT browning, but the relevance of these findings to human pathology is unknown PPAR ligands reduce obesity-associated comorbidities by acting on fat storage capacity of WAT and fat burning in BAT and/or peripheral tissues, thereby reducing ectopic fat overload PPARα and PPARγ ligands are clinically used for the treatment of dyslipidaemia and insulin resistance, respectively; in preclinical models, PPARβ/δ Agonists also improve atherogenic dyslipidaemia and insulin resistance Clinical trials using PPARγ Agonists show favourable effects in patients with nonalcoholic steatohepatitis, but the results are so far inconclusive The current challenge is to develop potent PPAR Agonists without adverse effects; Agonists targeting two or more PPARs that have a partial or selective gene activation pattern represent potential therapeutic approaches Obesity is a worldwide epidemic that predisposes individuals to cardiometabolic complications, such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), which are all related to inappropriate ectopic lipid deposition. Identification of the pathogenic molecular mechanisms and effective therapeutic approaches are highly needed. The peroxisome proliferator-activated receptors (PPARs) modulate several biological processes that are perturbed in obesity, including inflammation, lipid and glucose metabolism and overall energy homeostasis. Here, we review how PPARs regulate the functions of adipose tissues, such as adipogenesis, lipid storage and adaptive thermogenesis, under healthy and pathological conditions. We also discuss the clinical use and mechanism of PPAR Agonists in the treatment of obesity comorbidities such as dyslipidaemia, T2DM and NAFLD. First generation PPAR Agonists, primarily those acting on PPARγ, are associated with adverse effects that outweigh their clinical benefits, which led to the discontinuation of their development. An improved understanding of the physiological roles of PPARs might, therefore, enable the development of safe, new PPAR Agonists with improved therapeutic potential. Peroxisome proliferator-activated receptors (PPARs) are integrators of both inflammatory and metabolic signalling networks. In this Review, the authors provide a comprehensive overview of how PPARs contribute to the development of metabolic disorders and how pharmacologically targeting these pathways can be used to develop new therapeutics for such diseases.

  • on the mechanism for PPAR Agonists to enhance abca1 gene expression
    Atherosclerosis, 2009
    Co-Authors: Masaki Ogata, Frank J Gonzalez, Bart Staels, Maki Tsujita, Mohammad Anwar Hossain, Nobukatsu Akita, Shogo Suzuki, Tatsuya Fukutomi
    Abstract:

    Abstract Expression of ATP binding cassette transporter A1 (ABCA1), a major regulator of high density lipoprotein (HDL) biogenesis, is known to be up-regulated by the transcription factor liver X receptor (LXR) α, and expression is further enhanced by activation of the peroxisome proliferator activated receptors (PPARs). We investigated this complex regulatory network using specific PPAR Agonists: four fibrates (fenofibrate, bezafibrate, gemfibrozil and LY518674), a PPAR δ agonist (GW501516) and a PPAR γ agonist (pioglitazone). All of these compounds increased the expression of LXRs, PPARs and ABCA1 mRNAs, and associated apoA-I-mediated lipid release in THP-1 macrophage, WI38 fibroblast and mouse fibroblast. When mouse fibroblasts lacking expression of PPAR α were examined, the effects of fenofibrate and LY518674 were markedly diminished while induction by other ligands were retained. The PPAR α promoter was activated by all of these compounds in an LXR α-dependent manner, and partially in a PPAR α-dependent manner, in mouse fibroblast. The LXR responsive element (LXRE)-luciferase activity was enhanced by all the compounds in an LXR α-dependent manner in mouse fibroblast. This activation was exclusively PPAR α-dependent by fenofibrate and LY518674, but nonexclusively by the others. We conclude that PPARs and LXRs are involved in the regulation of ABCA1 expression and HDL biogenesis in a cooperative signal transduction pathway.

  • On the mechanism for PPAR Agonists to enhance ABCA1 gene expression.
    Atherosclerosis, 2009
    Co-Authors: Masaki Ogata, Frank J Gonzalez, Bart Staels, Maki Tsujita, Mohammad Anwar Hossain, Nobukatsu Akita, Shogo Suzuki, Tatsuya Fukutomi, Genjiro Kimura, Shinji Yokoyama
    Abstract:

    Expression of ATP binding cassette transporter A1 (ABCA1), a major regulator of high density lipoprotein (HDL) biogenesis, is known to be up-regulated by the transcription factor liver X receptor (LXR) alpha, and expression is further enhanced by activation of the peroxisome proliferator activated receptors (PPARs). We investigated this complex regulatory network using specific PPAR Agonists: four fibrates (fenofibrate, bezafibrate, gemfibrozil and LY518674), a PPAR delta agonist (GW501516) and a PPAR gamma agonist (pioglitazone). All of these compounds increased the expression of LXRs, PPARs and ABCA1 mRNAs, and associated apoA-I-mediated lipid release in THP-1 macrophage, WI38 fibroblast and mouse fibroblast. When mouse fibroblasts lacking expression of PPAR alpha were examined, the effects of fenofibrate and LY518674 were markedly diminished while induction by other ligands were retained. The PPAR alpha promoter was activated by all of these compounds in an LXR alpha-dependent manner, and partially in a PPAR alpha-dependent manner, in mouse fibroblast. The LXR responsive element (LXRE)-luciferase activity was enhanced by all the compounds in an LXR alpha-dependent manner in mouse fibroblast. This activation was exclusively PPAR alpha-dependent by fenofibrate and LY518674, but nonexclusively by the others. We conclude that PPARs and LXRs are involved in the regulation of ABCA1 expression and HDL biogenesis in a cooperative signal transduction pathway.

  • PPAR Agonists and the metabolic syndrome.
    Therapie, 2007
    Co-Authors: Bart Staels
    Abstract:

    Cardiovascular disease is significantly increased in patients with the metabolic syndrome and type 2 diabetes. A clustering of risk factors, including dyslipidemia, insulin resistance, hypertension, inflammation and coagulation disorders are likely to promote cardiovascular events in these patients. Peroxisome proliferator-activated receptors (PPARs) represent one important pathway that influence vascular function both directly and indirectly by altering gene expression. Indeed, PPAR activation induces beneficial effects not only on glucose homeostasis and lipid metabolism but also on endothelial function and vessel wall inflammation. PPAR Agonists such as fibrates (PPARalpha) and insulin-sensitizing thiazolidinediones (PPARgamma) are in clinical use and may alter the process of atherosclerosis, especially in subjects with the metabolic syndrome and type 2 diabetes. This review will highlight the emerging evidence for the beneficial effects of PPAR Agonists in the prevention and treatment of atherosclerosis in such high-risk patients.

  • PPAR Agonists: multimodal drugs for the treatment of type-2 diabetes
    Best practice & research. Clinical endocrinology & metabolism, 2007
    Co-Authors: Barbara Gross, Bart Staels
    Abstract:

    Patients with type-2 diabetes mellitus (T2DM) are considered to be at particularly high risk for cardiovascular disease. Over the last decade, the members of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors have emerged as valuable pharmacological targets whose activation can normalize metabolic dysfunctions and reduce some cardiovascular risk factors associated with T2DM. PPARα Agonists, such as the fibrates, can correct dyslipidemia. PPARγ Agonists, such as the thiazolidinediones, act as insulin sensitizers and improve insulin resistance in patients with T2DM. Because of restricted potency and certain side-effects of PPAR Agonists, as well as the increasingly epidemic incidence of T2DM, there is a real need for the development of selective PPAR Agonists with improved clinical efficacy. This chapter focuses on the PPAR Agonists currently used in the clinic, as well as on the discovery and development of the next generation of PPAR Agonists.

Chia Hui Lin - One of the best experts on this subject based on the ideXlab platform.

  • Structural basis for the improved potency of peroxisome proliferator-activated receptor (PPAR) Agonists.
    ChemMedChem, 2010
    Co-Authors: Yi Hui Peng, Mohane Selvaraj Coumar, Jiun Shyang Leou, Hui Yi Shiao, Chia Hui Lin, Wen-hsing Lin, Tzu Wen Lien, Xin Chen, John T.a. Hsu
    Abstract:

    The need to develop safer and more effective antidiabetic drugs is essential owing to the growth worldwide of the diabetic population. Targeting the PPAR receptor is one strategy for the treatment of diabetes; the PPAR Agonists rosiglitazone and pioglitazone are already on the market. Here we report the identification of a potent PPAR agonist, 15, whose PPARγ activation was more than 20 times better than that of rosiglitazone. Compound 15 was designed to incorporate an indole head with a carboxylic acid group, and 4-phenylbenzophenone tail to achieve a PPARγ EC 50 of 10 nM. Compound 15 showed the most potent PPARγ agonist activity among the compounds we investigated. To gain molecular insight into the improved potency of 15, a structural biology study and binding energy calculations were carried out. Superimposition of the X-ray structures of 15 and agonist 10 revealed that, even though they have the same indole head part, they adopt different conformations. The head part of 15 showed stronger interactions toward PPARγ; this could be due to the presence of the novel tail part 4-phenylbenzophenone, which could enhance the binding efficiency of 15 to PPARγ.

  • Structural basis for the structure-activity relationships of peroxisome proliferator-activated receptor Agonists
    Journal of medicinal chemistry, 2006
    Co-Authors: Neeraj Mahindroo, Yi Hui Peng, Chia Hui Lin, Tzu Wen Lien, John T.a. Hsu, Uan-kang Tan, Ekambaranellore Prakash, Hong-jen Lee, Xin Chen
    Abstract:

    Type 2 diabetes has rapidly reached an epidemic proportion becoming a major threat to global public health. PPAR Agonists have emerged as a leading class of oral antidiabetic drugs. We report a structure biology analysis of novel indole-based PPAR Agonists to explain the structure-activity relationships and present a critical analysis of reasons for change in selectivity with change in the orientation of the same scaffolds. The results would be helpful in designing novel PPAR Agonists.

  • indol 1 yl acetic acids as peroxisome proliferator activated receptor Agonists design synthesis structural biology and molecular docking studies
    Journal of Medicinal Chemistry, 2006
    Co-Authors: Neeraj Mahindroo, Tzu Wen Lien, Chiungchiu Wang, Chunchen Liao, Chienfu Huang, Yihuei Peng, Weijan Huang, Yingting Lin, Mingchen Hsu, Chia Hui Lin
    Abstract:

    A series of novel indole-based PPAR Agonists is described leading to discovery of 10k, a highly potent PPAR pan-agonist. The structural biology and molecular docking studies revealed that the distances between the acidic group and the linker, when a ligand was complexed with PPARgamma protein, were important for the potent activity. The hydrophobic tail part of 10k makes intensive hydrophobic interaction with the PPARgamma protein resulting in potent activity.

Paul S. Humphries - One of the best experts on this subject based on the ideXlab platform.

Xin Chen - One of the best experts on this subject based on the ideXlab platform.

  • Structural basis for the improved potency of peroxisome proliferator-activated receptor (PPAR) Agonists.
    ChemMedChem, 2010
    Co-Authors: Yi Hui Peng, Mohane Selvaraj Coumar, Jiun Shyang Leou, Hui Yi Shiao, Chia Hui Lin, Wen-hsing Lin, Tzu Wen Lien, Xin Chen, John T.a. Hsu
    Abstract:

    The need to develop safer and more effective antidiabetic drugs is essential owing to the growth worldwide of the diabetic population. Targeting the PPAR receptor is one strategy for the treatment of diabetes; the PPAR Agonists rosiglitazone and pioglitazone are already on the market. Here we report the identification of a potent PPAR agonist, 15, whose PPARγ activation was more than 20 times better than that of rosiglitazone. Compound 15 was designed to incorporate an indole head with a carboxylic acid group, and 4-phenylbenzophenone tail to achieve a PPARγ EC 50 of 10 nM. Compound 15 showed the most potent PPARγ agonist activity among the compounds we investigated. To gain molecular insight into the improved potency of 15, a structural biology study and binding energy calculations were carried out. Superimposition of the X-ray structures of 15 and agonist 10 revealed that, even though they have the same indole head part, they adopt different conformations. The head part of 15 showed stronger interactions toward PPARγ; this could be due to the presence of the novel tail part 4-phenylbenzophenone, which could enhance the binding efficiency of 15 to PPARγ.

  • Structural basis for the structure-activity relationships of peroxisome proliferator-activated receptor Agonists
    Journal of medicinal chemistry, 2006
    Co-Authors: Neeraj Mahindroo, Yi Hui Peng, Chia Hui Lin, Tzu Wen Lien, John T.a. Hsu, Uan-kang Tan, Ekambaranellore Prakash, Hong-jen Lee, Xin Chen
    Abstract:

    Type 2 diabetes has rapidly reached an epidemic proportion becoming a major threat to global public health. PPAR Agonists have emerged as a leading class of oral antidiabetic drugs. We report a structure biology analysis of novel indole-based PPAR Agonists to explain the structure-activity relationships and present a critical analysis of reasons for change in selectivity with change in the orientation of the same scaffolds. The results would be helpful in designing novel PPAR Agonists.