Activation of Peroxisome Proliferator-activated Receptor α Induces Lysosomal Biogenesis in Brain Cells

Lee

The Journal of Immunology

et al. 2017

131

155

The role of peroxisome proliferator–activated receptor α (PPAR-α) in innate host defense is largely unknown. In this study, we show that PPAR-α is essential for antimycobacterial responses via activation of transcription factor EB (TFEB) transcription and inhibition of lipid body formation. PPAR-α deficiency resulted in an increased bacterial load and exaggerated inflammatory responses during mycobacterial infection. PPAR-α agonists promoted autophagy, lysosomal biogenesis, phagosomal maturation, and antimicrobial defense against Mycobacterium tuberculosis or M. bovis bacillus Calmette–Guérin. PPAR-α agonists regulated multiple genes involved in autophagy and lysosomal biogenesis, including Lamp2, Rab7, and Tfeb in bone marrow–derived macrophages. Silencing of TFEB reduced phagosomal maturation and antimicrobial responses, but increased macrophage inflammatory responses during mycobacterial infection. Moreover, PPAR-α activation promoted lipid catabolism and fatty acid β-oxidation in macrophages during mycobacterial infection. Taken together, our data indicate that PPAR-α mediates antimicrobial responses to mycobacterial infection by inducing TFEB and lipid catabolism.

Section: Discussionmentioning

confidence: 99%

PPAR-α Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism

Lee

The Journal of Immunology

et al. 2017

131

155

Journal of Cell Science

“…Interestingly, PPARα activation with its agonist pirinixic acid (Wy-14643) reduces proinflammatory responses by promoting activation of autophagy in a mouse model of acute liver failure (Jiao et al, 2014). Activation of PPARα by gemfibrozil also upregulates the expression of TFEB, which, in turn, transcriptionally increases the levels of ATG proteins (Ghosh et al, 2015). PPARγ is also a master regulator of adipocyte differentiation (Jonker et al, 2012).…”

Section: Jun -Activated By Diverse Stressesmentioning

confidence: 99%

Transcriptional regulation of mammalian autophagy at a glance

Füllgrabe

Ghislat

Cho

et al. 2016

170

171

Macroautophagy, hereafter referred to as autophagy, is a catabolic process that results in the lysosomal degradation of cytoplasmic contents ranging from abnormal proteins to damaged cell organelles. It is activated under diverse conditions, including nutrient deprivation and hypoxia. During autophagy, members of the core autophagy-related (ATG) family of proteins mediate membrane rearrangements, which lead to the engulfment and degradation of cytoplasmic cargo. Recently, the nuclear regulation of autophagy, especially by transcription factors and histone modifiers, has gained increased attention. These factors are not only involved in rapid responses to autophagic stimuli, but also regulate the long-term outcome of autophagy. Now there are more than 20 transcription factors that have been shown to be linked to the autophagic process. However, their interplay and timing appear enigmatic as several have been individually shown to act as major regulators of autophagy. This Cell Science at a Glance article and the accompanying poster highlights the main cellular regulators of transcription involved in mammalian autophagy and their target genes.

“…These investigations strongly support a CNS role of PPAR-a in neuroprotection against oxidative damage, by controlling superoxide anion removal (by SOD1), and hydrogen peroxide generation (by SOD1 and ACOX1) and removal (by CAT). At the cellular level, the biogenesis or functionality of mitochondria, peroxisomes and even lysosomes are indeed regulated by PPARa and its cofactors particularly peroxisome proliferator activated receptor gamma co-activator 1 alpha (PGC1a) (Fidaleo et al 2014;Ghosh et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Pterostilbene ameliorates intracerebroventricular streptozotocin induced memory decline in rats

2016

There is strong evidence that mitochondrial dysfunction mediated oxidative stress results in aging and energy metabolism deficits thus playing a prime role in pathogenesis of Alzheimer's disease, neuronal death and cognitive dysfunction. Evidences accrued in empirical studies suggest the antioxidant, anticancer and anti-inflammatory activities of the phytochemical pterostilbene (PTS). PTS also exhibits favourable pharmacokinetic attributes compared to other stilbenes. Hence, in the present study, we explored the neuroprotective role of PTS in ameliorating the intracerebroventricular administered streptozotocin (STZ) induced memory decline in rats. PTS at doses of 10, 30 and 50 mg/kg, was administered orally to STZ administered Sprague-Dawley (SD) rats. The learning and memory tests, Morris water maze test and novel object recognition test were performed which revealed improved cognition on PTS treatment. Further, there was an overall improvement in brain antioxidant parameters like elevated catalase and superoxide dismutase activities, GSH levels, lowered levels of nitrites, lipid peroxides and carbonylated proteins. There was improved cholinergic transmission as evident by decreased acetylcholinesterase activities. The action of ATPases (Na ? K ? , Ca 2? and Mg 2? ) indicating the maintenance of cell membrane potential was also augmented. mRNA expression of battery of genes involved in cellular mitochondrial biogenesis and inflammation showed variations which extrapolate to hike in mitochondrial biogenesis and abated inflammation. The histological findings corroborated the effective role of PTS in countering STZ induced structural aberrations in brain.