GW0742 (PPAR-beta agonist) attenuates hepatic endoplasmic reticulum stress by improving hepatic energy metabolism in high-fat diet fed mice

Silva-Veiga, Flávia Maria; Rachid, Tamiris Lima; Oliveira, Letícia de; Graus-Nunes, Francielle; Mandarim-de-Lacerda, Carlos Alberto; Souza-Mello, Vanessa

doi:10.1016/j.mce.2018.03.013

Cited by 30 publications

(17 citation statements)

References 54 publications

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“…Since FA metabolism appears to be strongly influenced by PPARβ/δ target genes in other cell types (Silva‐Veiga et al, ), we next determined whether the endogenous FA energy metabolism of iPSC‐astrocytes is regulated by the PPARβ/δ‐agonist, GW0742. Treatment with 1 μM GW0742 for 24 hr in the presence of limited exogenous energy substrates reversed the impairment in the maximal utilization of endogenous FAs in PSEN1 ΔE 9 astrocytes and returned the OCR to that of control astrocytes, resulting in genotype × treatment interaction ( F (1, 8) = 33.5, p = .0004, two‐way ANOVA ; Figure d).…”

Section: Resultsmentioning

confidence: 99%

PPARβ/δ‐agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes

Konttinen

Gureviciene

Oksanen

et al. 2018

Glia

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Astrocytes are the gatekeepers of neuronal energy supply. In neurodegenerative diseases, bioenergetics demand increases and becomes reliant upon fatty acid oxidation as a source of energy. Defective fatty acid oxidation and mitochondrial dysfunctions correlate with hippocampal neurodegeneration and memory deficits in Alzheimer's disease (AD), but it is unclear whether energy metabolism can be targeted to prevent or treat the disease. Here we show for the first time an impairment in fatty acid oxidation in human astrocytes derived from induced pluripotent stem cells of AD patients. The impairment was corrected by treatment with a synthetic peroxisome proliferator activated receptor delta (PPARβ/δ) agonist GW0742 which acts to regulate an array of genes governing cellular metabolism. GW0742 enhanced the expression of CPT1a, the gene encoding for a rate‐limiting enzyme of fatty acid oxidation. Similarly, treatment of a mouse model of AD, the APP/PS1‐mice, with GW0742 increased the expression of Cpt1a and concomitantly reversed memory deficits in a fear conditioning test. Although the GW0742‐treated mice did not show altered astrocytic glial fibrillary acidic protein‐immunoreactivity or reduction in amyloid beta (Aβ) load, GW0742 treatment increased hippocampal neurogenesis and enhanced neuronal differentiation of neuronal progenitor cells. Furthermore, GW0742 prevented Aβ‐induced impairment of long‐term potentiation in hippocampal slices. Collectively, these data suggest that PPARβ/δ‐agonism alleviates AD related deficits through increasing fatty acid oxidation in astrocytes and improves cognition in a transgenic mouse model of AD.

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Section: Resultsmentioning

confidence: 99%

PPARβ/δ‐agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes

Konttinen

Gureviciene

Oksanen

et al. 2018

Glia

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“…PPARβ/δ agonist L165041 and GW501516 increased hepatic expression of fibrosis markers in carbon tetrachloride (CCl 4 )-injected mice [60,61], but not the agonist KD3010. Therefore, PPARβ/δ-specific agonists are attractive because PPARβ/δ activation can attenuate dyslipidemia, insulin resistance, hepatic steatosis, and inflammation [47,48,[62][63][64].…”

Section: Lessons From Liver-specific Ppard-null Micementioning

confidence: 99%

PPARs as Metabolic Regulators in the Liver: Lessons from Liver-Specific PPAR-Null Mice

Wang

Nakajima

Gonzalez

et al. 2020

IJMS

348

243

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Peroxisome proliferator-activated receptor (PPAR) α, β/δ, and γ modulate lipid homeostasis. PPARα regulates lipid metabolism in the liver, the organ that largely controls whole-body nutrient/energy homeostasis, and its abnormalities may lead to hepatic steatosis, steatohepatitis, steatofibrosis, and liver cancer. PPARβ/δ promotes fatty acid β-oxidation largely in extrahepatic organs, and PPARγ stores triacylglycerol in adipocytes. Investigations using liver-specific PPAR-disrupted mice have revealed major but distinct contributions of the three PPARs in the liver. This review summarizes the findings of liver-specific PPAR-null mice and discusses the role of PPARs in the liver.

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“…The activation of PPARβ/δ by GW501516 also prevents the inflammation associated with ER stress in skeletal muscle cells and ameliorates insulin resistance in mice through an adenosine monophosphate-activated protein kinase (AMPK)-dependent mechanism[ 164 ]. The PPAR-β/δ agonist GW0742 also reportedly attenuates ER stress by improving hepatic energy metabolism in the livers of high fat diet-administered mice[ 165 ]. The effectiveness of agonists for PPAR-α/δ has been confirmed in NASH patients as well[ 166 ].…”

Section: Non-alcoholic Fatty Liver Disease As a Representative Injurymentioning

confidence: 99%

Mutual interaction between oxidative stress and endoplasmic reticulum stress in the pathogenesis of diseases specifically focusing on non-alcoholic fatty liver disease

Fujii

Homma

Kobayashi

et al. 2018

WJBC

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Reactive oxygen species (ROS) are produced during normal physiologic processes with the consumption of oxygen. While ROS play signaling roles, when they are produced in excess beyond normal antioxidative capacity this can cause pathogenic damage to cells. The majority of such oxidation occurs in polyunsaturated fatty acids and sulfhydryl group in proteins, resulting in lipid peroxidation and protein misfolding, respectively. The accumulation of misfolded proteins in the endoplasmic reticulum (ER) is enhanced under conditions of oxidative stress and results in ER stress, which, together, leads to the malfunction of cellular homeostasis. Multiple types of defensive machinery are activated in unfolded protein response under ER stress to resolve this unfavorable situation. ER stress triggers the malfunction of protein secretion and is associated with a variety of pathogenic conditions including defective insulin secretion from pancreatic β-cells and accelerated lipid droplet formation in hepatocytes. Herein we use nonalcoholic fatty liver disease (NAFLD) as an illustration of such pathological liver conditions that result from ER stress in association with oxidative stress. Protecting the ER by eliminating excessive ROS via the administration of antioxidants or by enhancing lipid-metabolizing capacity via the activation of peroxisome proliferator-activated receptors represent promising therapeutics for NAFLD.

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GW0742 (PPAR-beta agonist) attenuates hepatic endoplasmic reticulum stress by improving hepatic energy metabolism in high-fat diet fed mice

Cited by 30 publications

References 54 publications

PPARβ/δ‐agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes

PPARβ/δ‐agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes

PPARs as Metabolic Regulators in the Liver: Lessons from Liver-Specific PPAR-Null Mice

Mutual interaction between oxidative stress and endoplasmic reticulum stress in the pathogenesis of diseases specifically focusing on non-alcoholic fatty liver disease

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