The effects of n-6 polyunsaturated fatty acid deprivation on the inflammatory gene response to lipopolysaccharide in the mouse hippocampus

Alashmali, Shoug; Lin, Lin; Trépanier, Marc-Olivier; Cisbani, Giulia; Bazinet, Richard P.

doi:10.1186/s12974-019-1615-0

Cited by 13 publications

(8 citation statements)

References 42 publications

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“…PUFAs are classified as n-3 and n-6 PUFAs according to the location of the double bonds. The derivates from n-3 PUFAs have anti-inflammatory and immunomodulatory properties (Weylandt et al, 2012;Calder, 2015), whereas those from n-6 PUFAs are generally known to have pro-inflammatory effects (Alashmali et al, 2019). Some specific n-6 PUFA changes related to SLE were discovered in this study.…”

Section: Discussionmentioning

confidence: 63%

“…Some species of FA can affect the inflammatory state of the body. For example, linoleic acid and arachidonic acid (AA) have pro-inflammatory effects (Alashmali et al, 2019), while docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have anti-inflammatory and immunomodulatory properties (Weylandt et al, 2012;Calder, 2015). Previous studies have found that abnormal FA levels are associated with insulin resistance and atherosclerosis (Lepretti et al, 2018;Steffen et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Metabolic Profiling Reveals an Abnormal Pattern of Serum Fatty Acids in MRL/lpr Mice Under Treatment With Prednisone

Zhou

Zhang

et al. 2020

Front. Pharmacol.

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Glucocorticoids (GCs) are commonly used to treat systemic lupus erythematosus (SLE). Unfortunately, excessive GCs can induce many side effects associated with disordered fatty acid (FA) metabolism. Although an increased level of total FA has been found after GCs treatment, it is not clear whether all FA species increased or only certain FA species were altered. A gas chromatography-mass spectrometry-based FA profiling approach was performed to reveal the alterations of FA species in SLE model mice (MRL/lpr) after treatment with 5 mg/kg of prednisone. The study showed a distinct FA profile in MRL/lpr mice compared to the controls, mainly manifested by elevated polyunsaturated FAs (arachidonate, docosahexaenoate, etc.), which are related to the inflammatory state; and altered (product FA/precursor FA) ratios representing the estimated activities of FA desaturase and elongase (higher activities of multiple elongases, △4 desaturase, △5 desaturase, △6 desaturase, and lower activity of △8 desaturase). Treatment with 5 mg/ kg of prednisone decreased the total level of n-6 polyunsaturated FA in MRL/lpr mice; in particular, the level of arachidonate and estimated activity of △5 desaturase were reduced to the control level. Moreover, prednisone induced additional perturbations in FAs, including not only saturated FAs, but also monounsaturated FAs and n-3 polyunsaturated FAs, indicating that there was a strong effect of prednisone on FA metabolism. These results may be valuable for further studies of the side effects of GCs treatment.

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Metabolic Profiling Reveals an Abnormal Pattern of Serum Fatty Acids in MRL/lpr Mice Under Treatment With Prednisone

Zhou

Zhang

et al. 2020

Front. Pharmacol.

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“…Although it is commonly recognized that n-6 PUFA has pro-in ammatory functions as prostaglandin and leukotriene precursors, n-6 PUFA can also be converted into anti-in ammatory mediators or modulate the gene expression of the pro-in ammatory cytokine to exert anti-in ammatory effects. Alashmali et al reported that adequate dietary n-6 PUFA intake restored hippocampal in ammation cytokine gene expression caused by intra-cerebroventricular lipopolysaccharide (LPS) injection [53]. We, therefore, speculate that the AD-like pathology in APP/PS1 mice might have caused hyperactivated neuroin ammation in the brain, which could be antagonized by the treatment with HFD.…”

Section: Discussionmentioning

confidence: 84%

Effects of Distinct n-6 to n-3 Polyunsaturated Fatty Acid Rations on Insulin Resistant and AD-like Phenotypes in High-Fat Diets-Fed APP/PS1 Transgenic Mice

Guo

et al. 2021

Preprint

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Background: Type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) are two prevalent diseases with comparable pathophysiological features and genetic predisposition. Polyunsaturated fatty acids (PUFAs) are essential in maintaining normal brain function. However, little is known about the impact of dietary n-6/n-3 PUFA ratio on AD-like pathology, especially in high-fat diet (HFD)-fed AD model mice. Methods: In the present study, the APP/PS1 mice were treated with 60% HFD for 3.5 months to induced insulin resistance. After that, 45% HFD with different n-6/n-3 PUFA ratios (n-6/n-3=1:1, 5:1 or 16:1) was applied for additional 3.5 months treatment. Following the dietary intervention, the behavior of mice was observed using the Water maze. Following behavioral testing, the animals were euthanized, and serum and tissue samples were collected for biochemical, histological and pathological analyses and evaluation. Cortical fatty acid profile was measured by gas chromatography. Western Blot and immunohistochemistry methods were used to detect protein expression of molecules related to AD pathology and insulin signaling pathway(s) in the brain sample tissues. Immunofluorescence assay was used to uncover the expression and migration of NF-κB in the cortex. qPCR method was applied to determine the gene expression of cortical pro-inflammatory cytokines.Results: HFD caused insulin resistance, increased serum IL-6 and TNF-α level, elevated cortical soluble Aβ1-40, Aβ1-42 content, and increased brain n-6/n-3 PUFAs ratio in APP/PS1 mice. Increased APP and BACE1 protein expression and p-IR/IR ratio, but decreased pro-inflammatory cytokines mRNA expression was observed in the cortex from 60% HFD-fed APP/PS1 mice. N-3 PUFAs rich diet (n-6/n-3=1:1) relieved insulin resistance and hyperlipidemia induced by 60% HFD. Cortical soluble Aβ1-40 and Aβ1-42 contents, the expression of cortical APP, GLUT3, insulin metabolism related molecules, and NF-κB pathway downstream pro-inflammatory cytokines showed a dietary n-6/n-3 PUFAs ratio-dependent way, indicating that dietary n-6/n-3 PUFA ratio plays a critical role in modifying the responses of serum inflammatory cytokine, AD pathology, cortical n-6/n-3 PUFAs ratio, insulin signaling and neuroinflammation to HFD treatment.Conclusion: Dietary n-6/n-3 PUFA ratio play an important role in modifying AD pathophysiology, insulin signaling pathway, and neuro-inflammation response to high fat diet treatment in brain.

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“…The number of astrocytes was positively correlated with the expression of Mfs2a in the brain (Tiwary et al, 2018). Alashmali et al (2019) found that the upregulation of Mfsd2a in mice adequately fed with N-6 PUFA is possibly due to the high presence of astrocytes, maintaining Mfsd2a expression in the brain and controlling BBB homeostasis. In the future, studies on Mfsd2a-knockout mice are expected to clarify the mechanism by which N-6 PUFA affects the expression of Mfsd2a in the brain.…”

Section: Alzheimer's Diseasementioning

confidence: 86%

The Role of Mfsd2a in Nervous System Diseases

Huang

2021

Front. Neurosci.

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Major facilitator superfamily (MFS) is the maximum and most diversified membrane transporter, acting as uniporters, symporters and antiporters. MFS is considered to have a good development potential in the transport of drugs for the treatment of brain diseases. The major facilitator superfamily domain containing protein 2a (Mfsd2a) is a member of MFS. Mfsd2a-knockout mice have shown a marked decrease of docosahexaenoic acid (DHA) level in brain, exhibiting neuron loss, microcephaly and cognitive deficits, as DHA acts essentially in brain growth and integrity. Mfsd2a has attracted more and more attention in the study of nervous system diseases because of its critical role in maintaining the integrity of the blood-brain barrier (BBB) and transporting DHA, including inhibiting cell transport in central nervous system endothelial cells, alleviating BBB injury, avoiding BBB injury in cerebral hemorrhage model, acting as a carrier etc. Up to now, the clinical research of Mfsd2a in nervous system diseases is rare. This article reviewed the current research progress of Mfsd2a in nervous system diseases. It summarized the physiological functions of Mfsd2a in the occurrence and development of intracranial hemorrhage (ICH), Alzheimer’s disease (AD), sepsis-associated encephalopathy (SAE), autosomal recessive primary microcephaly (MCPH) and intracranial tumor, aiming to provide ideas for the basic research and clinical application of Mfsd2a.

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The effects of n-6 polyunsaturated fatty acid deprivation on the inflammatory gene response to lipopolysaccharide in the mouse hippocampus

Cited by 13 publications

References 42 publications

Metabolic Profiling Reveals an Abnormal Pattern of Serum Fatty Acids in MRL/lpr Mice Under Treatment With Prednisone

Metabolic Profiling Reveals an Abnormal Pattern of Serum Fatty Acids in MRL/lpr Mice Under Treatment With Prednisone

Effects of Distinct n-6 to n-3 Polyunsaturated Fatty Acid Rations on Insulin Resistant and AD-like Phenotypes in High-Fat Diets-Fed APP/PS1 Transgenic Mice

The Role of Mfsd2a in Nervous System Diseases

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