Palmitic acid but not palmitoleic acid induces insulin resistance in a human endothelial cell line by decreasing SERCA pump expression

Vazquez-Jimenez, J. Gustavo; Chávez-Reyes, Jesús; Romero‐García, Tatiana; Zarain‐Herzberg, Ángel; Valdés-Flores, Jesús; Galindo-Rosales, José Manuel; Rueda, Angélica; Guerrero‐Hernández, Agustín; Olivares-Reyes, J. Alberto

doi:10.1016/j.cellsig.2015.10.001

Cited by 37 publications

(44 citation statements)

References 45 publications

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“…As one of most abundant FFAs in plasma, palmitate is closely associated with pathogenesis and progression of insulin resistance in insulin-target tissues and cells through inducing oxidative stress, ER stress, and inflammation (Jung et al, 2015; Ly et al, 2017). The previous studies have also demonstrated the inhibitory impacts of the elevated palmitate concentration on cell function and insulin signaling of endothelial cells (Kim et al, 2005; Lu et al, 2013; Gustavo Vazquez-Jimenez et al, 2016). Consistent with these views, we found that palmitate induced insulin resistance in HUVECs in time- and concentration-dependent manners ( Figures 1A,B ).…”

Section: Discussionmentioning

confidence: 87%

“…Palmitate acid (P0500, Sigma-Aldrich, St. Louis, MO, USA) was dissolved in ethanol, mixed with 20% of free fatty acid (FFA)-free BSA, and then incubated overnight at 4°C. Insulin resistance was induced as previously described (Gustavo Vazquez-Jimenez et al, 2016). Briefly, HUVECs were plated in 6-well plates or 60 mm dishes until cells have reached 80% confluence and then incubated with serum-free Medium 200 for another 6 h before palmitate supplementation.…”

Section: Methodsmentioning

confidence: 99%

“…Long-term or inappropriate UPR has a direct causal relationship with insulin resistance (Marciniak and Ron, 2006; Hotamisligil, 2010). Previous studies have shown a significant association between ER stress and insulin resistance in endothelial cells (Lenna et al, 2014; Gustavo Vazquez-Jimenez et al, 2016). When this ER stress is blocked pharmacologically, a complete recovery of insulin sensitivity is achieved (Ozcan et al, 2004).…”

Section: Introductionmentioning

confidence: 95%

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RETRACTED: Curcumin Improves Palmitate-Induced Insulin Resistance in Human Umbilical Vein Endothelial Cells by Maintaining Proteostasis in Endoplasmic Reticulum

Qian

Zhang

et al. 2017

Front. Pharmacol.

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Dysfunction of proteasome and autophagy will result in disturbance of endoplasmic reticulum (ER) proteostasis, and thus lead to long-term and chronic ER stress and subsequent unfolded protein response (UPR), which is implicated in the occurrence and development of insulin resistance. Curcumin exerts beneficial metabolic effects in in vitro cells and in vivo animal models of diabetes and diabetic complications including cardiovascular diseases, due to its powerful anti-oxidative and anti-inflammatory properties. However, its impacts on insulin resistance of endothelial cells and its underlying mechanism(s) remain ill-defined. Herein, we tested the hypothesis that curcumin action in ER protein quality control was related to improvement of insulin resistance in human umbilical vein endothelial cells (HUVECs) cultured with saturated fatty acid palmitate. We found that palmitate treatment induced insulin resistance of HUVECs and activated both the ubiquitin-proteasome system (UPS) and autophagy. Palmitate-stimulated activation of the UPS and autophagy was attenuated by pharmacological inhibition of ER stress. In addition, curcumin supplementation mitigated palmitate-induced insulin resistance, inhibited the UPS, and activated autophagy. Furthermore, curcumin administration suppressed palmitate-induced protein aggregation and ER stress. Genetic inhibition of autophagy by silencing autophagy protein 5 (Atg5) completely restored total protein ubiquitination and protein aggregation in HUVECs treated with combined curcumin and palmitate. Atg5-knockdown also abolished the beneficial effects of curcumin on palmitate-induced ER stress, JNK/IRS-1 pathway as well as insulin signaling. Our results reveal that curcumin-activated autophagy could maintain proteostasis in ER leading to attenuation of ER stress and subsequent inhibition of JNK/IRS-1 pathway and improvement of insulin resistance.

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Section: Discussionmentioning

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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RETRACTED: Curcumin Improves Palmitate-Induced Insulin Resistance in Human Umbilical Vein Endothelial Cells by Maintaining Proteostasis in Endoplasmic Reticulum

Qian

Zhang

et al. 2017

Front. Pharmacol.

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“…Elevated plasma triglyceride (TG) or free fatty acid (FFA) are recognized risk factors of diabetes, because of their actions on insulin sensitivity in peripheral tissues5678910111213. In plasma, fatty acid (FA) molecules are bound to albumin molecules and become water-soluble.…”

mentioning

confidence: 99%

TNF-α stimulates endothelial palmitic acid transcytosis and promotes insulin resistance

Yang

Zheng

et al. 2017

Sci Rep

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Persistent elevation of plasma TNF-α is a marker of low grade systemic inflammation. Palmitic acid (PA) is the most abundant type of saturated fatty acid in human body. PA is bound with albumin in plasma and could not pass through endothelial barrier freely. Albumin-bound PA has to be transported across monolayer endothelial cells through intracellular transcytosis, but not intercellular diffusion. In the present study, we discovered that TNF-α might stimulate PA transcytosis across cardiac microvascular endothelial cells, which further impaired the insulin-stimulated glucose uptake by cardiomyocytes and promoted insulin resistance. In this process, TNF-α-stimulated endothelial autophagy and NF-κB signaling crosstalk with each other and orchestrate the whole event, ultimately result in increased expression of fatty acid transporter protein 4 (FATP4) in endothelial cells and mediate the increased PA transcytosis across microvascular endothelial cells. Hopefully the present study discovered a novel missing link between low grade systemic inflammation and insulin resistance.

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“…The present study showed that EMP treatment could affect the expression level of Atp2a2, and qPCR validation showed that EMP treatment could increase the expression level of Atp2a2. Furthermore, the upregulation of SERCA2 expression could increase insulin sensitivity and improve insulin resistance (25,26), suggesting that the enhancement of insulin sensitivity of EMP may also related to the upregulated of Atp2a2.…”

Section: Discussionmentioning

confidence: 99%

Liver Transcriptomic Reveals Novel Pathways of Empagliflozin Associated With Type 2 Diabetic Rats

Xiang

et al. 2020

Front. Endocrinol.

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The hypoglycaemic target of empagliflozin (EMP), as a novel inhibitor of sodium-glucose cotransporter (SGLT2), is clear. However, recent studies have shown that EMP also has an important role in lipid metabolism and cardiovascular diseases. The liver plays an important role in the development of type 2 diabetes (T2D), although whether EMP affects liver glucose metabolism is currently not reported. This study was designed to evaluate the effect of EMP on hepatic glucose metabolism in T2D and the underlying mechanism. A model of T2D was established by a high-fat and glucose diet (HFD) combined with streptozotocin (30 mg/kg) in male Wistar rats. Serum samples were collected to measure biochemical indicators, and liver samples were extracted for RNA-seq assay. Quantitative real-time PCR (qPCR) was used to further verify the gene expression levels detected by the RNA-seq assay. The EMP group showed significantly decreased blood glucose, triglyceride, cholesterol, non-esterified fatty acid and low-density lipoprotein cholesterol levels, and increased high-density lipoprotein cholesterol levels in serum compared with the type 2 diabetes model (MOD) group. Furthermore, EMP decreased the levels of inflammatory factors IL-1β, IL-6, and IL-8 in the serum compared to the MOD. Liver transcriptome analysis showed EMP affects a large number of upregulated and downregulated genes. Some of these genes are novel and involve in the metal ion binding pathway and the negative regulation of transcription from the RNA polymerase II promoter pathway, which are also closely related to glucolipid metabolism and insulin signaling. Our study provides new knowledge about the mechanism through which SGLT inhibitor can offer beneficial effects in T2D and especially in the hepatic metabolism. These genes found in this study also laid a solid foundation for further research on the new roles and mechanisms of EMP.

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Palmitic acid but not palmitoleic acid induces insulin resistance in a human endothelial cell line by decreasing SERCA pump expression

Cited by 37 publications

References 45 publications

RETRACTED: Curcumin Improves Palmitate-Induced Insulin Resistance in Human Umbilical Vein Endothelial Cells by Maintaining Proteostasis in Endoplasmic Reticulum

RETRACTED: Curcumin Improves Palmitate-Induced Insulin Resistance in Human Umbilical Vein Endothelial Cells by Maintaining Proteostasis in Endoplasmic Reticulum

TNF-α stimulates endothelial palmitic acid transcytosis and promotes insulin resistance

Liver Transcriptomic Reveals Novel Pathways of Empagliflozin Associated With Type 2 Diabetic Rats

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