Hypoxia worsens the impact of intracellular triglyceride accumulation promoted by electronegative low-density lipoprotein in cardiomyocytes by impairing perilipin 5 upregulation

Revuelta‐López, Elena; Cal, Roi; Julve, Josep; Rull, Anna; Martínez-Bujidos, M.; Pérez-Cuellar, Montserrat; Ordóñez-Llanos, Jordi; Badimon, Lina; Sánchez-Quesada, José Luis; Llorente‐Cortés, Vicenta

doi:10.1016/j.biocel.2015.06.014

Cited by 11 publications

(10 citation statements)

References 58 publications

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“…Moreover, TG accumulation was promoted in a time-dependent manner; this suggests that this process is not down-regulated over the assay timeframes. This surprising ability of LDL(−) to store intracellular TG has also been described in cardiomyocytes [37]. LDL(−)-induced TG-enriched LDs are probably not only due to the TG content in LDL(−), which is much lower than that of cholesterol, but also to their increased non-esterified fatty acid (NEFA) content, which can contribute to TG synthesis.…”

Section: Discussionmentioning

confidence: 64%

Electronegative LDL Promotes Inflammation and Triglyceride Accumulation in Macrophages

Puig

Montolio²,

Camps‐Renom

et al. 2020

Cells

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Electronegative low-density lipoprotein (LDL) (LDL(−)), a modified LDL that is present in blood and exerts atherogenic effects on endothelial cells and monocytes. This study aimed to determine the action of LDL(−) on monocytes differentiated into macrophages. LDL(−) and in vitro-modified LDLs (oxidized, aggregated, and acetylated) were added to macrophages derived from THP1 monocytes over-expressing CD14 (THP1-CD14). Then, cytokine release, cell differentiation, lipid accumulation, and gene expression were measured by ELISA, flow cytometry, thin-layer chromatography, and real-time PCR, respectively. LDL(−) induced more cytokine release in THP1-CD14 macrophages than other modified LDLs. LDL(−) also promoted morphological changes ascribed to differentiated macrophages. The addition of high-density lipoprotein (HDL) and anti-TLR4 counteracted these effects. LDL(−) was highly internalized by macrophages, and it was the major inductor of intracellular lipid accumulation in triglyceride-enriched lipid droplets. In contrast to inflammation, the addition of anti-TLR4 had no effect on lipid accumulation, thus suggesting an uptake pathway alternative to TLR4. In this regard, LDL(−) upregulated the expression of the scavenger receptors CD36 and LOX-1, as well as several genes involved in triglyceride (TG) accumulation. The importance and novelty of the current study is that LDL(−), a physiologically modified LDL, exerted atherogenic effects in macrophages by promoting differentiation, inflammation, and triglyceride-enriched lipid droplets formation in THP1-CD14 macrophages, probably through different receptors.

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Section: Discussionmentioning

confidence: 64%

Electronegative LDL Promotes Inflammation and Triglyceride Accumulation in Macrophages

Puig

Montolio²,

Camps‐Renom

et al. 2020

Cells

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“…Hypoxia is also considered an important contributing factor in the development of some diabetes-induced complications, such as retinopathy, cardiovascular disease or impaired wound (Dissemond et al, 2015;Revuelta-Lopez et al, 2015;Semeraro et al, 2015). Unlike Nrf2 that upregulates the antioxidant potential of cells, hypoxiainducible factors-1α and -2α (HIF1α, HIF2α) regulate the transcription of other groups of gene that preserve and protect cells and tissues exposed to hypoxic conditions .…”

Section: Protective Mechanisms Against Oxidative Stressoxidative Condmentioning

confidence: 99%

Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells

Maulucci

Daniel

Cohen

et al. 2016

Molecular Aspects of Medicine

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“…By using native electronegative LDL, we have demonstrated that the most electronegative subfraction, L5, is the only one capable of inducing endothelial cell apoptosis ( 15 , 16 ), platelet aggregation ( 17 ), C-reactive protein overproduction ( 18 ), and impairment of endothelial cell regeneration ( 19 , 20 ). Other investigators have also reported that electronegative LDL can promote TG accumulation in cardiomyocytes ( 21 ) and induce inflammasome activation in human macrophages ( 22 ). Plasma L5 levels are elevated in patients with high cardiovascular risks, such as hypercholesterolemia and type 2 diabetes ( 15 , 20 ).…”

mentioning

confidence: 98%

Electronegative low density lipoprotein induces renal apoptosis and fibrosis: STRA6 signaling involved

Chen

Chan

et al. 2016

Journal of Lipid Research

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Dyslipidemia has been proven to capably develop and aggravate chronic kidney disease. We also report that electronegative LDL (L5) is the most atherogenic LDL. On the other hand, retinoic acid (RA) and RA receptor (RAR) agonist are reported to be beneficial in some kidney diseases. “Stimulated by retinoic acid 6” (STRA6), one retinol-binding protein 4 receptor, was recently identified to regulate retinoid homeostasis. Here, we observed that L5 suppressed STRA6 cascades [STRA6, cellular retinol-binding protein 1 (CRBP1), RARs, retinoid X receptor α, and retinol, RA], but L5 simultaneously induced apoptosis and fibrosis (TGFβ1, Smad2, collagen 1, hydroxyproline, and trichrome) in kidneys of L5-injected mice and L5-treated renal tubular cells. These L5-induced changes of STRA6 cascades, renal apoptosis, and fibrosis were reversed in kidneys of LOX1−/− mice. LOX1 RNA silencing and inhibitor of c-Jun N-terminal kinase and p38MAPK rescued the suppression of STRA6 cascades and apoptosis and fibrosis in L5-treated renal tubular cells. Furthermore, crbp1 gene transfection reversed downregulation of STRA6 cascades, apoptosis, and fibrosis in L5-treated renal tubular cells. For mimicking STRA6 deficiency, efficient silencing of STRA6 RNA was performed and was found to repress STRA6 cascades and caused apoptosis and fibrosis in L1-treated renal tubular cells. In summary, this study reveals that electronegative L5 can cause kidney apoptosis and fibrosis via the suppression of STRA6 cascades, and implicates that STRA6 signaling may be involved in dyslipidemia-mediated kidney disease.

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Hypoxia worsens the impact of intracellular triglyceride accumulation promoted by electronegative low-density lipoprotein in cardiomyocytes by impairing perilipin 5 upregulation

Cited by 11 publications

References 58 publications

Electronegative LDL Promotes Inflammation and Triglyceride Accumulation in Macrophages

Electronegative LDL Promotes Inflammation and Triglyceride Accumulation in Macrophages

Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells

Electronegative low density lipoprotein induces renal apoptosis and fibrosis: STRA6 signaling involved

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