Peroxisome Proliferator-Activated Receptors Features, Functions, and Future

Youssef, Jihan; Badr, Mostafa Z.

doi:10.11131/2015/101188

Cited by 11 publications

(7 citation statements)

References 299 publications

(399 reference statements)

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“…2E, panel iii). Altogether, these data suggested that AA-driven stabilization of PPAR␣ could shift the equilibrium of PPAR␣ toward the active configurations resulting in higher interactions with different co-regulators, thus augmenting activation of PPAR␣-driven transcriptional machinery (45,46).…”

Section: Discussionmentioning

confidence: 86%

Arjunolic acid, a peroxisome proliferator-activated receptor α agonist, regresses cardiac fibrosis by inhibiting non-canonical TGF-β signaling

Bansal

Chatterjee

Singh

et al. 2017

Journal of Biological Chemistry

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Cardiac hypertrophy and associated heart fibrosis remain a major cause of death worldwide. Phytochemicals have gained attention as alternative therapeutics for managing cardiovascular diseases. These include the extract from the plant which is a popular cardioprotectant and may prevent or slow progression of pathological hypertrophy to heart failure. Here, we investigated the mode of action of a principal bioactive compound, arjunolic acid (AA), in ameliorating hemodynamic load-induced cardiac fibrosis and identified its intracellular target. Our data revealed that AA significantly represses collagen expression and improves cardiac function during hypertrophy. We found that AA binds to and stabilizes the ligand-binding domain of peroxisome proliferator-activated receptor α (PPARα) and increases its expression during cardiac hypertrophy. PPARα knockdown during AA treatment in hypertrophy samples, including angiotensin II-treated adult cardiac fibroblasts and renal artery-ligated rat heart, suggests that AA-driven cardioprotection primarily arises from PPARα agonism. Moreover, AA-induced PPARα up-regulation leads to repression of TGF-β signaling, specifically by inhibiting TGF-β-activated kinase1 (TAK1) phosphorylation. We observed that PPARα directly interacts with TAK1, predominantly via PPARα N-terminal transactivation domain (AF-1) thereby masking the TAK1 kinase domain. The AA-induced PPARα-bound TAK1 level thereby shows inverse correlation with the phosphorylation level of TAK1 and subsequent reduction in p38 MAPK and NF-κBp65 activation, ultimately culminating in amelioration of excess collagen synthesis in cardiac hypertrophy. In conclusion, our findings unravel the mechanism of AA action in regressing hypertrophy-associated cardiac fibrosis by assigning a role of AA as a PPARα agonist that inactivates non-canonical TGF-β signaling.

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Section: Discussionmentioning

confidence: 86%

Arjunolic acid, a peroxisome proliferator-activated receptor α agonist, regresses cardiac fibrosis by inhibiting non-canonical TGF-β signaling

Bansal

Chatterjee

Singh

et al. 2017

Journal of Biological Chemistry

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“…Furthermore, in the cytosol, the protein can interact directly with kinases, i.e., MEK1 and PKC α , and cytochrome c reductase [ 66 – 69 ]. The advantage of such DNA-independent mechanisms is enrooted at the basis of a relative fast initiation of desired cellular effects, whereas a DNA-dependent mode of action can take hours due to their genomic processing structure [ 70 ]. Therefore, for a fast establishment of a specific M Φ phenotype, the presence of a redox-modified PPAR γ could be beneficial.…”

Section: Discussionmentioning

confidence: 99%

Redox Regulation of PPARγ in Polarized Macrophages

et al. 2020

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The peroxisome proliferator-activated receptor (PPARγ) is a central mediator of cellular lipid metabolism and immune cell responses during inflammation. This is facilitated by its role as a transcription factor as well as a DNA-independent protein interaction partner. We addressed how the cellular redox milieu in the cytosol and the nucleus of lipopolysaccharide (LPS)/interferon-γ- (IFNγ-) and interleukin-4- (IL4-) polarized macrophages (MΦ) initiates posttranslational modifications of PPARγ, that in turn alter its protein function. Using the redox-sensitive GFP2 (roGFP2), we validated oxidizing and reducing conditions following classical and alternative activation of MΦ, while the redox status of PPARγ was determined via mass spectrometry. Cysteine residues located in the zinc finger regions (amino acid fragments AA 90-115, AA 116-130, and AA 160-167) of PPARγ were highly oxidized, accompanied by phosphorylation of serine 82 in response to LPS/IFNγ, whereas IL4-stimulation provoked minor serine 82 phosphorylation and less cysteine oxidation, favoring a reductive milieu. Mutating these cysteines to alanine to mimic a redox modification decreased PPARγ-dependent reporter gene transactivation supporting a functional shift of PPARγ associated with the MΦ phenotype. These data suggest distinct mechanisms for regulating PPARγ function based on the redox state of MΦ.

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“…Ketiga, kurkumin berperan pula dalam induksi dan ekspresi HO-1 (Heme Oxygenase), subunit glutation dan NAD(P)H:quinone oxidoreductase 1. Keempat, kurkumin membuka dan mengaktivasi anion channels, depolarisassi potensial membran sehingga menghasilkan produksi elektron dan memicu insulin keluar dari sel β pankreas (Zhang et al 2013) Mekanisme kurkumin terhadap PPARγ Peroxisome proliferator-activated receptors (PPAR) adalah faktor transkripsi yang berperan penting dalam diferensiasi sel dan beberapa proses metabolisme, terutama pada proses metabolisme lemak dan keseimbangan glukosa di dalam tubuh (Fuentes et al 2013;Lefterova et al 2014;Youssef and Badr 2015). Secara molekuler, aktivasi dari PPAR akan menyebabkan inhibisi faktor transkripsi NF-κB yang akan menurunkan banyak ekspresi gen seperti AP-1, p53, CREB, c-Myc, Wnt13, Dok-4, HMGA1, and c-Src (Grygiel-Górniak 2014).…”

Section: Kurkumin Terhadap Diabetes Tipeunclassified

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Malik¹,

Ulma²,

Sarmoko

et al. 2021

Acta Pharm Indo

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Diabetes mellitus (DM) is a chronic disease with a prevalence of 8.3% of the total population worldwide. One of the active compounds currently being developed to treat DM is curcumin. Curcumin is a compound obtained from the perennial plant of the zingiberaceae family containing the active compound of polyphenols and have potential as antitumor, antioxidant, anti-inflammatory, and antidiabetic compounds. Curcumin proved to have functional efficacy in hyperglycaemia, type 1 and 2 diabetes mellitus, diabetic neuropathy, diabetic nephropathy and pancreatic beta cell dysfunction. At the molecular level, the function of curcumin involves several pathways including to the nuclear factor-kappa B (NF-kB), PPARγ, and free fatty acids.

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Peroxisome Proliferator-Activated Receptors Features, Functions, and Future

Cited by 11 publications

References 299 publications

Arjunolic acid, a peroxisome proliferator-activated receptor α agonist, regresses cardiac fibrosis by inhibiting non-canonical TGF-β signaling

Arjunolic acid, a peroxisome proliferator-activated receptor α agonist, regresses cardiac fibrosis by inhibiting non-canonical TGF-β signaling

Redox Regulation of PPARγ in Polarized Macrophages

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