PPARγ Agonists Attenuate Palmitate-Induced ER Stress through Up-Regulation of SCD-1 in Macrophages

Ikeda, Jiro; Ichiki, Toshihiro; Takahara, Yusuke; Kojima, Hiroshi; Sankoda, Chikahiro; Kitamoto, Shiro; Tokunou, Tomotake; Sunagawa, Kenji

doi:10.1371/journal.pone.0128546

Cited by 46 publications

(27 citation statements)

References 34 publications

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“…This protective role of desaturation has been indeed demonstrated in some in vitro studies and further supported by the findings in SCD1 muscle transgenic mice . It is to be noted that SCD1 knock‐out mice are resistant to diet‐induced weight gain and obesity‐related metabolic disease , but it is due to a defective synthesis of TGs and cholesteryl esters in the lean animals and does not contradict the importance of acyl‐CoA desaturation in the cells under the pressure of high FFA levels.…”

Section: Discussionsupporting

confidence: 61%

Investigation of the putative rate‐limiting role of electron transfer in fatty acid desaturation using transfected HEK293T cells

et al. 2019

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Elevated fatty acid (FA) levels contribute to severe metabolic diseases. Unbalanced oversupply of saturated FAs is particularly damaging, which renders stearoyl‐CoA desaturase (SCD1) activity an important factor of resistance. A SCD1‐related oxidoreductase protects cells against palmitate toxicity, so we aimed to test whether desaturase activity is limited by SCD1 itself or by the associated electron supply. Unsaturated/saturated FA ratio was markedly elevated by SCD1 overexpression while it remained unaffected by the overexpression of SCD1‐related electron transfer proteins in HEK293T cells. Electron supply was not rate‐limiting either in palmitate‐treated cells or in cells with enhanced SCD1 expression. Our findings indicate the rate‐limiting role of SCD1 itself, and that FA desaturation cannot be facilitated by reinforcing the electron supply of the enzyme.

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Section: Discussionsupporting

confidence: 61%

Investigation of the putative rate‐limiting role of electron transfer in fatty acid desaturation using transfected HEK293T cells

et al. 2019

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“…In addition, we observed an increase in FAS mRNA and a tendency to increase SREBP1 and SCD1 in HFT RG KO mice. The activation of SCD1 in macrophages by rosiglitazone is an important pathway to reduce endoplasmic reticulum stress, thus decreasing cellular apoptosis, and depletory events (Ikeda et al, ). Furthermore, we showed an increase in PGC‐1α gene expression, a PPAR co‐activator which regulates genes involved in energetic metabolism and mitochondrial biogenesis (Puigserver and Spiegelman, ).…”

Section: Discussionmentioning

confidence: 99%

Association Between Aerobic Exercise and Rosiglitazone Avoided the NAFLD and Liver Inflammation Exacerbated in PPAR‐α Knockout Mice

Batatinha

Lima

Teixeira

et al. 2016

Journal Cellular Physiology

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Nonalcoholic fatty liver disease (NAFLD) is one of the main liver diseases today, and may progress to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Some studies have shown the beneficial effects of aerobic exercise on reversing NAFLD. To verify whether chronic aerobic exercise improves the insulin resistance, liver inflammation, and steatohepatitis caused by a high fat diet (HF) and whether PPARα is involved in these actions. C57BL6 wild type (WT) and PPAR-α knockout (KO) mice were fed with a standard diet (SD) or HF during 12 weeks; the HF mice were trained on a treadmill during the last 8 weeks. Serum glucose and insulin tolerances, serum levels of aspartate aminotransferase, hepatic content of triacylglycerol, cytokines, gene expression, and protein expression were evaluated in all animals. Chronic exposure to HF diet increased triacylglycerol accumulation in the liver, leading to NAFLD, increased aminotransferase in the serum, increased peripheral insulin resistance, and higher adiposity index. Exercise reduced all these parameters in both animal genotypes. The liver lipid accumulation was not associated with inflammation; trained KO mice, however, presented a huge inflammatory response that was probably caused by a decrease in PPAR-γ expression. We conclude that exercise improved the damage caused by a HF independently of PPARα, apparently by a peripheral fatty acid oxidation in the skeletal muscle. We also found that the absence of PPARα together with exercise leads to a decrease in PPAR-γ and a huge inflammatory response. J. Cell. Physiol. 232: 1008-1019, 2017. © 2016 Wiley Periodicals, Inc.

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“…The relative mRNA levels were analyzed via the quantitative comparative Ct method and normalized with 18s gene expression as an internal control (Ikeda et al. ). The nucleotide sequences of primers are used:…”

Section: Methodsmentioning

confidence: 99%

Hypoxia‐inducible factor‐1αdeletion in myeloid lineage attenuates hypoxia‐induced pulmonary hypertension

et al. 2019

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Hypoxemia is seen in patients with pulmonary hypertension and hypoxic pulmonary vasoconstriction worsens their clinical condition. However, vasoconstriction is not the only aspect through which hypoxia induces the progression to pulmonary hypertension. Hypoxia‐inducible factor‐1 α ( HIF ‐1 α ) is a transcription factor responding to hypoxic conditions by regulating hundreds of genes involved in angiogenesis, erythropoiesis, inflammation, and proliferation. We sought to determine the contribution of HIF ‐1 α in myeloid lineage cells to the pulmonary vascular response to chronic exposure to hypoxia. We generated myeloid‐specific HIF ‐1 α knockout (Mye HIF 1 KO ) mice by using Cre‐lox P system, and exposed them to hypoxic conditions for 3 weeks to induce pulmonary hypertension. Macrophages from Mye HIF 1 KO and control mice were used for western blotting, RT ‐ qPCR , chemotaxis assay, and ATP assay. Mye HIF 1 KO mice exposed to hypoxia for 3 weeks exhibited a significant reduction in the right ventricular systolic pressure accompanied by a decrease in the ratio of the right ventricular weight to left ventricular weight, muscularization of the small pulmonary arteries, and infiltration of macrophages into the lung and right ventricle compared with control mice. HIF ‐1 α ‐deficient peritoneal macrophages showed less migration toward monocyte chemoattractant protein‐1 and a decrease in intracellular ATP levels. These results indicate that HIF ‐1 α in macrophages contributes to the progression of pulmonary vascular remodeling and pulmonary hypertension induced by chronic exposure to hypoxic conditions. The inhibition of myeloid‐specific HIF ‐1 α may be a novel therapeutic strategy for the treatment of pulmonary hypertension.

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PPARγ Agonists Attenuate Palmitate-Induced ER Stress through Up-Regulation of SCD-1 in Macrophages

Cited by 46 publications

References 34 publications

Investigation of the putative rate‐limiting role of electron transfer in fatty acid desaturation using transfected HEK293T cells

Investigation of the putative rate‐limiting role of electron transfer in fatty acid desaturation using transfected HEK293T cells

Association Between Aerobic Exercise and Rosiglitazone Avoided the NAFLD and Liver Inflammation Exacerbated in PPAR‐α Knockout Mice

Hypoxia‐inducible factor‐1αdeletion in myeloid lineage attenuates hypoxia‐induced pulmonary hypertension

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