Managing the Dyslipidemia of Metabolic Syndrome: Beyond Statin Therapy

Jialal, Ishwarlal; Smith, G. J.

doi:10.1089/met.2012.1500

Cited by 3 publications

(4 citation statements)

References 13 publications

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“…In the present study, we focussed on PPARγ receptor, as it plays a critical extensive role over broad spectrum of diseases such as type 2 diabetes mellitus, inflammatory diseases, Alzheimer’s disease, and in some cancers [17–23]. PPARγ comprises a Y-shaped ligand binding domain (LBD), which is segmented into three arms, arm I, arm II and arm III.…”

Section: Introductionmentioning

confidence: 99%

Probing the intermolecular interactions of PPARγ-LBD with polyunsaturated fatty acids and their anti-inflammatory metabolites to infer most potential binding moieties

et al. 2017

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BackgroundPPARγ is an isoform of peroxisome proliferator-activated receptor (PPAR) belonging to a super family of nuclear receptors. PPARγ receptor is found to play a crucial role in the modulation of lipid and glucose homeostasis. Its commotion has been reported to play a significant role in a broad spectrum of diseases such as type 2 diabetes mellitus, inflammatory diseases, Alzheimer’s disease, and in some cancers. Hence, PPARγ is an important therapeutic target. Polyunsaturated fatty acids (PUFAs) and their metabolites (henceforth referred to as bioactive lipids) are known to function as agonists of PPARγ. However, agonistic binding modes and affinity of these ligands to PPARγ are yet to be deciphered.MethodsIn this study, we performed a comparative molecular docking, binding free energy calculation and molecular dynamics simulation to infer and rank bioactive lipids based on the binding affinities with the ligand binding domain (LBD) of PPARγ.ResultsThe results inferred affinity in the order of resolvin E1 > neuroprotectin D1 > hydroxy-linoleic acid > docosahexaenoic acid > lipoxin A4 > gamma-linolenic acid, arachidonic acid > alpha-linolenic acid > eicosapentaenoic acid > linoleic acid. Of all the bioactive lipids studied, resolvin E1, neuroprotectin D1 and hydroxy-linoleic acid showed significant affinity comparable to proven PPARγ agonist namely, rosiglitazone, in terms of Glide XP docking score, H-bond formation with the key residues, binding free energy and stable complex formation with LBD favouring co-activator binding, as inferred through Molecular Dynamics trajectory analysis.ConclusionHence, these three bioactive lipids (resolvin E1, neuroprotectin D1 and hydroxy-linoleic acid) may be favourably considered as ideal drug candidates in therapeutic modulation of clinical conditions such as type 2 DM, Alzheimer’s disease and other instances where PPARγ is a key player.

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Section: Introductionmentioning

confidence: 99%

Probing the intermolecular interactions of PPARγ-LBD with polyunsaturated fatty acids and their anti-inflammatory metabolites to infer most potential binding moieties

et al. 2017

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“…From the pathological point of view, these receptors are related to metabolic diseases (mainly, type 2 diabetes mellitus, metabolic syndrome and dyslipidemia) [9–11], inflammatory process [12,13], neurodegeneration [14] and some kinds of cancer [15–17]. …”

Section: Introductionmentioning

confidence: 99%

Structure-Based Virtual Screening and Discovery of New PPARδ/γ Dual Agonist and PPARδ and γ Agonists

2015

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Peroxisome proliferator-activated receptors (PPARs) are involved in the control of carbohydrate and lipid metabolism and are considered important targets to treat diabetes mellitus and metabolic syndrome. The available PPAR ligands have several side effects leading to health risks justifying the search for new bioactive ligands to activate the PPAR subtypes, in special PPARδ, the less studied PPAR isoform. Here, we used a structure-based virtual screening protocol in order to find out new PPAR ligands. From a lead-like subset of purchasable compounds, we identified 5 compounds with potential PPAR affinity and, from preliminary in vitro assays, 4 of them showed promising biological activity. Therefore, from our in silico and in vitro protocols, new PPAR ligands are potential candidates to treat metabolic diseases.

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“…1 Despite the concern for increased risk of development of new-onset diabetes, statins remain the first-line treatment for lowering of LDL-C in patients with metabolic syndrome. 4,[9][10][11] Sattar et al found in their meta-analysis that the number needed to treat to prevent a cardiovascular event was 155 and the authors calculated that for every 3 patients in whom a cardiovascular event was likely to be prevented, 1 patient was likely to develop diabetes. 7 This risk/benefit profile as well as no clear established causal relationship between statins and new-onset diabetes is the reason that statins continue to be recommended as first-line treatment for dyslipidemia in metabolic syndrome.…”

mentioning

confidence: 99%

“…ameliorate this burden because they have antiinflammatory properties. 1,10,13 However, the risk for development of T2DM in patients with metabolic syndrome is an important consideration, particularly in patient groups who may be more susceptible, such as women, patients over 65 years of age, and certain ethnic groups with a greater risk for diabetes. 1 This leads us to ask, what other strategies should we examine that lower LDL in metabolic syndrome.…”

mentioning

confidence: 99%

Strategies to Lower Low-Density Lipoprotein Cholesterol in Metabolic Syndrome: Averting the Diabetes Risk

Sheely

Jialal²

2013

Metabolic Syndrome and Related Disorders

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Managing the Dyslipidemia of Metabolic Syndrome: Beyond Statin Therapy

Cited by 3 publications

References 13 publications

Probing the intermolecular interactions of PPARγ-LBD with polyunsaturated fatty acids and their anti-inflammatory metabolites to infer most potential binding moieties

Probing the intermolecular interactions of PPARγ-LBD with polyunsaturated fatty acids and their anti-inflammatory metabolites to infer most potential binding moieties

Structure-Based Virtual Screening and Discovery of New PPARδ/γ Dual Agonist and PPARδ and γ Agonists

Strategies to Lower Low-Density Lipoprotein Cholesterol in Metabolic Syndrome: Averting the Diabetes Risk

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