Fenofibrate improves high-fat diet-induced and palmitate-induced endoplasmic reticulum stress and inflammation in skeletal muscle

Dai, Fang; Tian, Jiang; Bao, Yingying; Chen, Guan-jun; Chen, Li; Zhang, Qiu; Lu, Yunxia

doi:10.1016/j.lfs.2016.06.008

Cited by 26 publications

(21 citation statements)

References 28 publications

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“…From our point of view, these effects are closely linked to the anti-inflammatory effects of Fen. These anti-inflammatory and protective effects have been previously evaluated in models of autoimmune myocarditis ( Cheng et al, 2016 ), skeletal muscle inflammation ( Dai et al, 2016 ), and cardiac ischemia/reperfusion ( Sugga et al, 2012 ). Moreover, we have previously demonstrated that a PPAR-γ agonist modulates the exacerbated heart inflammatory response using in vivo models of early lethal and non-lethal T. cruzi infection, as well as using in vitro models with a highly virulent T. cruzi strain ( Hovsepian et al, 2011 , Penas et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Treatment with Fenofibrate plus a low dose of Benznidazole attenuates cardiac dysfunction in experimental Chagas disease

Cevey

Mirkin

Donato

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

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Trypanosoma cruzi induces serious cardiac alterations during the chronic infection. Intense inflammatory response observed from the beginning of infection, is critical for the control of parasite proliferation and evolution of Chagas disease. Peroxisome proliferator-activated receptors (PPAR)-α, are known to modulate inflammation.In this study we investigated whether a PPAR-α agonist, Fenofibrate, improves cardiac function and inflammatory parameters in a murine model of T. cruzi infection. BALB/c mice were sequentially infected with two T. cruzi strains of different genetic background. Benznidazole, commonly used as trypanocidal drug, cleared parasites but did not preclude cardiac pathology, resembling what is found in human chronic chagasic cardiomyopathy. Fenofibrate treatment restored to normal values the ejection and shortening fractions, left ventricular end-diastolic, left ventricular end-systolic diameter, and isovolumic relaxation time. Moreover, it reduced cardiac inflammation and fibrosis, decreased the expression of pro-inflammatory (IL-6, TNF-α and NOS2) and heart remodeling mediators (MMP-9 and CTGF), and reduced serum creatine kinase activity. The fact that Fenofibrate partially inhibited NOS2 expression and NO release in the presence of a PPAR-α non-competitive inhibitor, suggested it also acted through PPAR-α-independent pathways. Since IκBα cytosolic degradation was inhibited by Fenofibrate, it can be concluded that the NFκB pathway has a role in its effects. Thus, we demonstrate that Fenofibrate acts through PPAR-α-dependent and -independent pathways.Our study shows that combined treatment with Fenofibrate plus Benznidazole is able both to reverse the cardiac dysfunction associated with the ongoing inflammatory response and fibrosis and to attain parasite clearance in an experimental model of Chagas disease.

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Section: Discussionmentioning

confidence: 99%

Treatment with Fenofibrate plus a low dose of Benznidazole attenuates cardiac dysfunction in experimental Chagas disease

Cevey

Mirkin

Donato

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

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“…Numerous studies have now clearly established that induction of ER stress in skeletal muscle can elicit insulin resistance (Quan et al 2015, Dai et al 2016, Kwak et al 2016, Liong & Lappas 2016. For example, tunicamycin or palmitate stimulated ER stress and insulin resistance while suppression of ER stress, using ER stress inhibitor tauroursodeoxycholic acid (TUDCA), melatonin or siRNA knockdown of IRE1α and GRP78, significantly downregulated insulin resistance in human skeletal muscle (Quan et al 2015, Dai et al 2016, Liong & Lappas 2016. The signaling protein tribbles 3 was shown to mediate endoplasmic reticulum stress-induced insulin resistance in skeletal muscle (Koh et al 2013).…”

Section: Discussionmentioning

confidence: 99%

“…For example, inflammation or high-fat diet can lead to ER stress (Dai et al 2016, Kwak et al 2016, Liong & Lappas 2016. Various reports have demonstrated that treatments which alleviate skeletal muscle ER stress induced by stressors such as highfat diet or palmitate are able to elicit a corresponding improvement in insulin sensitivity (Hwang et al 2013, Salvado et al 2014, Quan et al 2015, Dai et al 2016, Kwak et al 2016. To further elucidate the mechanisms responsible for adiponectin's insulin-sensitizing effect on skeletal muscle, additional research is needed to examine crosstalk between autophagy and ER stress.…”

Section: Introductionmentioning

confidence: 99%

Adiponectin improves insulin sensitivity via activation of autophagic flux

Ahlstrom

Rai

Chakma

et al. 2017

Journal of Molecular Endocrinology

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Skeletal muscle insulin resistance is known to play an important role in the pathogenesis of diabetes, and one potential causative cellular mechanism is endoplasmic reticulum (ER) stress. Adiponectin mediates anti-diabetic effects via direct metabolic actions and by improving insulin sensitivity, and we recently demonstrated an important role in stimulation of autophagy by adiponectin. However, there is limited knowledge on crosstalk between autophagy and ER stress in skeletal muscle and in particular how they are regulated by adiponectin. Here, we utilized the model of high insulin/glucose (HIHG)-induced insulin resistance, determined by measuring Akt phosphorylation (T308 and S473) and glucose uptake in L6 skeletal muscle cells. HIHG reduced autophagic flux measured by LC3 and p62 Western blotting and tandem fluorescent RFP/GFP-LC3 immunofluorescence (IF). HIHG also induced ER stress assessed by thioflavin T/KDEL IF, pIRE1, pPERK, peIF2α and ATF6 Western blotting and induction of a GRP78-mCherry reporter. Induction of autophagy by adiponectin or rapamycin attenuated HIHG-induced ER stress and improved insulin sensitivity. The functional significance of enhanced autophagy was validated by demonstrating a lack of improved insulin sensitivity in response to adiponectin in autophagy-deficient cells generated by overexpression of dominant negative mutant of Atg5. In summary, adiponectin-induced autophagy in skeletal muscle cells alleviated HIHG-induced ER stress and insulin resistance.

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“…Among UPR pathways, IRE1α, an ER bifunctional kinase/RNase has been shown to destabilize number of RNA and microRNA including miR-17-5p in pancreatic beta-cells[ 10 , 11 ]. Several studies reported the impact of HFD and its related metabolite such as free fatty acid in inducing ER-stress[ 15 - 17 ]. In the current study we were trying to decipher the underlying mechanisms that link HFD-mediated ER-stress to retinal inflammation.…”

Section: Introductionmentioning

confidence: 99%

High fat diet dysregulates microRNA-17-5p and triggers retinal inflammation: Role of endoplasmic-reticulum-stress

Coucha

Mohamed

Elshaer

et al. 2017

WJD

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AIMTo elucidate how high diet-induced endoplasmic reticulum-stress upregulates thioredoxin interacting protein expression in Müller cells leading to retinal inflammation.METHODSMale C57Bl/J mice were fed either normal diet or 60% high fat diet for 4-8 wk. During the 4 wk study, mice received phenyl-butyric acid (PBA); endoplasmic reticulum-stress inhibitor; for 2 wk. Insulin resistance was assessed by oral glucose tolerance. Effects of palmitate-bovine serum albumin (BSA) (400 μmol/L) were examined in retinal Müller glial cell line and primary Müller cells isolated from wild type and thioredoxin interacting protein knock-out mice. Expression of thioredoxin interacting protein, endoplasmic reticulum-stress markers, miR-17-5p mRNA, as well as nucleotide-binding oligomerization domain-like receptor protein (NLRP3) and IL1β protein was determined.RESULTSHigh fat diet for 8 wk induced obesity and insulin resistance evident by increases in body weight and impaired glucose tolerance. By performing quantitative real-time polymerase chain reaction, we found that high fat diet triggered the expression of retinal endoplasmic reticulum-stress markers (P < 0.05). These effects were associated with increased thioredoxin interacting protein and decreased miR-17-5p expression, which were restored by inhibiting endoplasmic reticulum-stress with PBA (P < 0.05). In vitro, palmitate-BSA triggered endoplasmic reticulum-stress markers, which was accompanied with reduced miR-17-5p and induced thioredoxin interacting protein mRNA in retinal Müller glial cell line (P < 0.05). Palmitate upregulated NLRP3 and IL1β expression in primary Müller cells isolated from wild type. However, using primary Müller cells isolated from thioredoxin interacting protein knock-out mice abolished palmitate-mediated increase in NLRP3 and IL1β.CONCLUSIONOur work suggests that targeting endoplasmic reticulum-stress or thioredoxin interacting protein are potential therapeutic strategies for early intervention of obesity-induced retinal inflammation.

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Fenofibrate improves high-fat diet-induced and palmitate-induced endoplasmic reticulum stress and inflammation in skeletal muscle

Cited by 26 publications

References 28 publications

Treatment with Fenofibrate plus a low dose of Benznidazole attenuates cardiac dysfunction in experimental Chagas disease

Treatment with Fenofibrate plus a low dose of Benznidazole attenuates cardiac dysfunction in experimental Chagas disease

Adiponectin improves insulin sensitivity via activation of autophagic flux

High fat diet dysregulates microRNA-17-5p and triggers retinal inflammation: Role of endoplasmic-reticulum-stress

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