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Adipose tissue dysfunction is associated with low levels of the novel Palmitic Acid Hydroxystearic Acids.

ABSTRACT: Adipose tissue dysfunction is considered an important contributor to systemic insulin resistance and Type 2 diabetes (T2D). Recently, a novel family of endogenous lipids, palmitic acid hydroxy stearic acids (PAHSAs), was discovered. These have anti-diabetic and anti-inflammatory effects in mice and are reduced in serum and adipose tissue of insulin resistant humans. In the present study, we investigate if adipose tissue dysfunction is associated with reduced PAHSA levels in human subjects and if PAHSAs influence adipocyte differentiation. Our results show that low expression of adipocyte GLUT4 and adipocyte hypertrophy, markers of adipose tissue dysfunction, are associated with reduced expression of key enzymes for de novo lipogenesis and adipose tissue levels of PAHSAs in human subjects. We also show that GLUT4 is not only a marker of adipose tissue dysfunction, but may be causally related to the observed impairments. PAHSAs may also act locally in the adipose tissue to improve adipogenesis through a mechanism bypassing direct activation of peroxisome proliferator-activated receptor (PPAR?). The discovery of PAHSAs and our current results provide novel insights into positive effects of lipid species in adipose tissue and mechanisms by which dysfunctional adipose tissue is associated with insulin resistance and risk of developing T2D.

SUBMITTER: Hammarstedt A

PROVIDER: S-EPMC6202399 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Adipose tissue dysfunction is associated with low levels of the novel Palmitic Acid Hydroxystearic Acids.

Hammarstedt Ann A Syed Ismail I Vijayakumar Archana A Eliasson Björn B Gogg Silvia S Kahn Barbara B BB Smith Ulf U

Scientific reports 20181025 1

Adipose tissue dysfunction is considered an important contributor to systemic insulin resistance and Type 2 diabetes (T2D). Recently, a novel family of endogenous lipids, palmitic acid hydroxy stearic acids (PAHSAs), was discovered. These have anti-diabetic and anti-inflammatory effects in mice and are reduced in serum and adipose tissue of insulin resistant humans. In the present study, we investigate if adipose tissue dysfunction is associated with reduced PAHSA levels in human subjects and if ...[more]

PMID: 30361530

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Project description:Background: Perivascular adipose tissue (PVAT) exerts anti-contractile effects on visceral arteries by release of various perivascular relaxing factors (PVRFs) and opening voltage-gated K+ (Kv) channels in vascular smooth muscle cells (VSMCs). Palmitic acid methyl ester (PAME) has been proposed as transferable PVRF in rat aorta. Here, we studied PVAT regulation of arterial tone of human mesenteric arteries and clarified the contribution of Kv channels and PAME in the effects. Methods: Wire myography was used to measure vasocontractions of mesenteric artery rings from patients undergoing abdominal surgery. Isolated aortic rings from Sprague-Dawley rats were studied for comparison. PVAT was either left intact or removed from the arterial rings. Vasocontractions were induced by external high K+ (60 mM), serotonin (5-HT) or phenylephrine. PAME (10 nM-3 ?M) was used as vasodilator. Kv channels were blocked by XE991, a Kv7 (KCNQ) channel inhibitor, or by 4-aminopyridine, a non-specific Kv channel inhibitor. PAME was measured in bathing solutions incubated with rat peri-aortic or human visceral adipose tissue. Results: We found that PVAT displayed anti-contractile effects in both human mesenteric arteries and rat aortas. The anti-contractile effects were inhibited by XE991 (30 ?M). PAME (EC50 ~1.4 ?M) was capable to produce relaxations of PVAT-removed rat aortas. These effects were abolished by XE991 (30 ?M), but not 4-aminopyridine (2 mM) or NDGA (10 ?M), a lipoxygenases inhibitor. The cytochrome P450 epoxygenase inhibitor 17-octadecynoic acid (ODYA 10 ?M) and the soluble epoxide hydrolase inhibitor 12-(3-adamantan-1-ylureido)-dodecanoic acid (AUDA 10 ?M) slightly decreased PAME relaxations. PAME up to 10 ?M failed to induce relaxations of PVAT-removed human mesenteric arteries. 5-HT induced endogenous PAME release from rat peri-aortic adipose tissue, but not from human visceral adipose tissue. Conclusions: Our data also suggest that Kv7 channels are involved in the anti-contractile effects of PVAT on arterial tone in both rat aorta and human mesenteric arteries. PAME could contribute to PVAT relaxations by activating Kv7 channels in rat aorta, but not in human mesenteric arteries.

Project description:BackgroundPalmitic acid (PA) has a lipotoxic effect on blood vessels, leading to endothelial dysfunction and cell death. The underlying mechanisms are not yet fully understood.AimWe sought to investigate the effects of PA on endothelial cells, with an emphasis on ferroptosis.MethodsRat corpus cavernosum endothelial cells (RCCECs) and human umbilical vein endothelial cells (HUVECs) were treated with PA to induce a pattern of cell death, as evidenced by the evaluation of cell viability. The differentially expressed genes were measured via RNA sequencing to reveal potential mechanisms. The intracellular levels of glutathione (GSH), malondialdehyde (MDA), ferrous ion (Fe2+), and reactive oxygen species (ROS) were evaluated using commercial kits. Western blot was performed to determine the expressions of relative proteins.OutcomesAt the end of the study period, the evaluated outcomes were cell viability, transcriptome profiles, the expressions of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), as well as levels of GSH, MDA, Fe2+, and ROS.ResultsPA-induced cell death of RCCECs and HUVECs was demonstrated in a dose- and time-dependent manner. Based on the findings of RNA-sequencing (RNA-seq), enrichment of many biological processes associated with cell cycle and response to stimulus occurred. More importantly, ferroptosis was highlighted in the bioinformatic analysis of both endothelial cells. The levels of intracellular Fe2+, MDA, and ROS were significantly increased following PA exposure while GSH was decreased, suggesting excessive iron accumulation, development of lipid peroxidation, and imbalanced redox homeostasis. Mechanistically, PA decreased the protein expression levels of GPX4 and SLC7A11 in endothelial cells, both of which played crucial roles in ferroptotic cell death.Clinical translationThis study suggests that ferroptosis may be a useful target for novel therapeutic interventions for endothelial dysfunction and cell death in vascular diseases such as erectile dysfunction.Strengths and limitationsIn this study, we found that ferroptosis could participate in PA-induced endothelial dysfunction and cell death. A limitation of the study is that it did not shed light on the overall mechanisms of this process. Therefore, further research on the intricate networks of regulating ferroptosis is needed.ConclusionOverall, the occurrence of ferroptosis was demonstrated in the PA-treated HUVECs and RCCECs in this study.

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Adipose tissue dysfunction is associated with low levels of the novel Palmitic Acid Hydroxystearic Acids.

Publications

Adipose tissue dysfunction is associated with low levels of the novel Palmitic Acid Hydroxystearic Acids.

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