N-3 polyunsaturated fatty acids: An innovative strategy against obesity and related metabolic disorders, intestinal alteration and gut microbiota dysbiosis
Obesity is now widely recognized to be associated with low-grade systemic inflammation. It has been shown that high-fat feeding modulates gut microbiota which strongly increased intestinal permeability leading to lipopolysaccharide absorption causing metabolic endotoxemia that triggers inflammation and metabolic disorders. N-3 polyunsaturated fatty acids (PUFAs) have been shown associated with anti-obesity properties, but results still remain heterogeneous and very few studies underlined the metabolic pathways involved. Thus, the use of Fat-1 transgenic mice allows to better understanding whether endogenous n-3 PUFAs enrichment contributes to obesity and associated metabolic disorders preve…
High pancreatic n-3 fatty acids prevent STZ-induced diabetes in fat-1 mice: inflammatory pathway inhibition.
OBJECTIVE Because of confounding factors, the effects of dietary n-3 polyunsaturated fatty acids (PUFA) on type 1 diabetes remain to be clarified. We therefore evaluated whether fat-1 transgenic mice, a well-controlled experimental model endogenously synthesizing n-3 PUFA, were protected against streptozotocin (STZ)-induced diabetes. We then aimed to elucidate the in vivo response at the pancreatic level. RESEARCH DESIGN AND METHODS β-Cell destruction was produced by multiple low-doses STZ (MLD-STZ). Blood glucose level, plasma insulin level, and plasma lipid analysis were then performed. Pancreatic mRNA expression of cytokines, the monocyte chemoattractant protein, and GLUT2 were evaluate…
Effects of streptozotocin and dietary fructose on delta-6 desaturation in spontaneously hypertensive rat liver.
We have investigated the effects of hypertension associated with diabetes mellitus on polyunsaturated fatty acid biosynthesis. For this purpose, two rat models for these pathologies have been established: a type 1 diabetic hypertensive model obtained by streptozotocin injection to spontaneously hypertensive rat (SHR), followed or not by insulin treatment (experiment 1); a type 2 diabetic hypertensive model by feeding SHR with a fructose enriched diet (experiment 2). Liver gene expression of delta-6 desaturase (D6D), microsomal D6D activities and fatty acid composition of total lipids were estimated. In experiment 1, an increase of linoleic acid (18:2 n-6) level was observed in the streptozo…
Effect of dietary polyunsaturated fatty acids on the expression of peroxisomal ABC transporters
Abstract Peroxisomal ABC transporters encoded by the ABCD genes are thought to participate in the import of specific fatty acids in the peroxisomal matrix. ABCD1 deficiency is associated with X-linked adrenoleukodystrophy (X-ALD), the most frequent peroxisomal disorder which is characterized by the accumulation of saturated very-long-chain fatty acids (VLCFA). ABCD2 (the closest homolog of ABCD1) and ABCD3 have been shown to have partial functional redundancy with ABCD1; only when overexpressed, they can compensate for VLCFA accumulation. Other lipids, for instance polyunsaturated fatty acids (PUFA), should be possible candidate substrates for the ABCD2 and ABCD3 gene products, ALDRP and PM…
n-3 polyunsaturated fatty acids and HER2-positive breast cancer: interest of the fat-1 transgenic mouse model over conventional dietary supplementation.
Overexpression of the tyrosine kinase receptor ErbB2/HER2/Neu, occurs in 25%-30% of invasive breast cancer (BC) with poor patient prognosis. Even if numerous studies have shown prevention of breast cancer by n-3 fatty acid intake, the experimental conditions under which n-3 fatty acids exert their protective effect have been variable from study to study, preventing unifying conclusions. Due to confounding factors, inconsistencies still remain regarding protective effects of n-3 polyunsaturated fatty acids (PUFA) on BC. When animals are fed with dietary supplementation in n-3 fatty acids (the traditional approach to modify tissue content and decrease the n-6/n-3 ratio) complex dietary intera…
Dehydroepiandrosterone up-regulates the Adrenoleukodystrophy-related gene (ABCD2) independently of PPAR alpha in rodents
International audience; X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disease caused by mutations in the ABCD1 gene, which encodes a peroxisomal ABC transporter, ALDP, supposed to participate in the transport of very long chain fatty acids (VLCFA). The adrenoleukodystrophyrelated protein (ALDRP), which is encoded by the ABCD2 gene, is the closest homolog of ALDP and is considered as a potential therapeutic target since functional redundancy has been demonstrated between the two proteins. Pharmacological induction of Abcd2 by fibrates through the activation of PPARa has been demonstrated in rodent liver. DHEA, the most abundant steroid in human, is described as a PPARa activat…
Inhibition of stearoyl-CoA desaturase 1 expression induces CHOP-dependent cell death in human cancer cells.
Background Cancer cells present a sustained de novo fatty acid synthesis with an increase of saturated and monounsaturated fatty acid (MUFA) production. This change in fatty acid metabolism is associated with overexpression of stearoyl-CoA desaturase 1 (Scd1), which catalyses the transformation of saturated fatty acids into monounsaturated fatty acids (e.g., oleic acid). Several reports demonstrated that inhibition of Scd1 led to the blocking of proliferation and induction of apoptosis in cancer cells. Nevertheless, mechanisms of cell death activation remain to be better understood. Principal Findings In this study, we demonstrated that Scd1 extinction by siRNA triggered abolition of de nov…
Trans-10, cis-12 conjugated linoleic acid induced cell death in human colon cancer cells through reactive oxygen species-mediated ER stress
Dietary conjugated linoleic acids (CLA) are fatty acid isomers with anticancer activities produced naturally in ruminants or from vegetable oil processing. The anticancer effects of CLA differ upon the cancer origin and the CLA isomers. In this study, we carried out to precise the effects of CLA isomers, c9,t11 and t10,c12 CLA, on mechanisms of cell death induction in colon cancer cells. We first showed that only t10,c12 CLA treatment (25 and 50μM) for 72h triggered apoptosis in colon cancer cells without affecting viability of normal-derived colon epithelial cells. Exposure of colon cancer cells to t10,c12 CLA activated ER stress characterized by induction of eIF2α phoshorylation, splicing…
Intestinal microbiota mediates the beneficial effects of n-3 polyunsaturated fatty acids during dietary obesity,
Obesity, now considered as a real worldwide epidemic affecting more than 650 million people, is complex and mainly associated with excessive energy intake and changes in eating habits favoring the consumption of diets rich in saturated fat and sugar. This multifactorial pathology is linked to chronic low grade systemic inflammation. Indeed, a high fat diet (HFD) leads to intestinal microbiota dysbiosis increasing gut permeability (partly attributed to a downregulation of genes encoding tight junction proteins) leading to an increase in bacterial lipopolysaccharides (LPS) levels so-called metabolic endotoxemia. Studies have shown that n-3 polyunsaturated fatty acids (PUFAs) are involved in t…
Fast high performance liquid chromatography analysis in lipidomics: Separation of radiolabelled fatty acids and phosphatidylcholine molecular species using a monolithic C18 silica column
Abstract HPLC procedures using conventional C 18 columns are usually used to separate simple and complex lipid mixtures but these methods of separation remain often laborious and very slow. Here, monolithic columns were successfully applied to separate lipids – radiolabelled fatty acid mixtures and individual phosphatidylcholine (PC) molecular species. For that, isocratic elution was performed using two Chromolith™ Performance RP-18e columns connected in series. Detection was achieved by online measurement of radioactivity for radiolabelled fatty acids and by UV absorbance at 205 nm for PC molecular species. The performances of such silica rods were compared to conventional reverse-phase si…
Retinal enrichment in omega-3 polyunsaturated fatty acids limits choroidal neovascularization
International audience; Purpose: Age-related Macular Degeneration (AMD) is the primary cause of blindness in elderly population of western countries. Prospective epidemiologic studies have reported that omega-3 polyunsaturated fatty acids (PUFAs) reduce the risk of progression to advanced AMD, and particularly to the neovascular forms. In this study, we have investigated the beneficial effects of omega-3 PUFA on choroidal neovascularization (CNV) in mice.Methods: Fat-1 mice, endogenously converting omega-6 to omega-3 PUFA, and littermate controls were used at 4 months of age. CNV was induced unilaterally in eye fundus by photocoagulation using a 532-nm laser. Confocal scanning laser ophthal…
Les acides gras trans : des acides gras bien singuliers
Cette revue resume des donnees experimentales ou cliniques recentes sur les acides gras trans, qui permettent de considerer certains d’entre eux comme des molecules bioactives d’interet – en particulier dans le domaine cardiovasculaire et en cancerologie –, susceptibles d’apporter une impulsion nouvelle aux applications industrielles relatives a leurs effets favorables sur la sante. Dans cette revue, nous soulignons l’emergence de divers aspects benefiques des acides gras trans naturels, qui ont des proprietes distinctes et parfois meme opposees a celles des acides gras trans retrouves dans les huiles partiellement hydrogenees. Ainsi, apres avoir ete mis en avant pour leurs effets deleteres…
Inhibition of the HER2 pathway by n-3 polyunsaturated fatty acids prevents breast cancer in fat-1 transgenic mice
Overexpression of the tyrosine kinase receptor, ErbB2/HER2/Neu, occurs in 25–30% of invasive breast cancer (BC) with poor patient prognosis. Due to confounding factors, inconsistencies still remain regarding the protective effects of n-3 polyunsaturated fatty acids (PUFAs) on BC. We therefore evaluated whether fat-1 transgenic mice, endogenously synthesizing n-3 PUFAs from n-6 PUFAs, were protected against BC development, and we then aimed to study in vivo a mechanism potentially involved in such protection. E0771 BC cells were implanted into fat-1 and wild-type (WT) mice. After tumorigenesis examination, we analyzed the expression of proteins involved in the HER2 signaling pathway and lipi…
Les oméga-3 préviennent l’altération de la couche de mucus, le stress du réticulum endoplasmique et l’inflammation induits par un régime obésogène au niveau du colon de souris fat-1
Introduction et but de l’etude Un regime obesogene induit d’importantes alterations de la barriere intestinale, une endotoxemie metabolique et une inflammation chronique dite de bas bruit. La couche de mucus recouvrant l’intestin, principalement constituee de la glycoproteine Muc2 produite par les cellules caliciformes, maintient les bacteries du microbiote a distance des cellules hotes, empechant ainsi une activation du systeme immunitaire. Il a ete montre qu’un regime obesogene etait capable d’alterer l’epaisseur de cette couche de mucus en association avec une inflammation et un stress du reticulum endoplasmique. Les omega-3 exercent de puissants effets anti-inflammatoires, et un enrichi…
Revisiting delta-6 desaturase regulation by C18 unsaturated fatty acids, depending on the nutritional status.
Dietary polyunsaturated fatty acids (PUFA) play a key role in regulating delta-6 desaturase (D6D), the key enzyme for long-chain PUFA biosynthesis. Nevertheless, the extent of their effects on this enzyme remains controversial and difficult to assess. It has been generally admitted that C18 unsaturated fatty acids (UFAs) regulate negatively delta-6 desaturase (D6D). This inhibition has been evidenced in regard to a high glucose/fat free (HG/FF) diet used in reference. However, several nutritional investigations did not evidence any inhibition of desaturases when feeding fatty acids. Because the choice of the basal diet appeared to be of primary importance in such experiments, our goal was t…
The metabolic cascade leading to eicosanoid precursors--desaturases, elongases, and phospholipases A2--is altered in Zucker fatty rats.
Abstract Metabolic syndrome characterized by insulin resistance and obesity is accompanied by severe lipid metabolism perturbations and chronic low-grade inflammation. However, many unresolved questions remained regarding the regulation that underlie dyslipidemia, particularly the regulation of the metabolic cascade (synthesis and release) leading to eicosanoid precursors release. This study was undertaken to investigate the regulation of desaturases/elongases and phospholipases A2 during the establishment of metabolic syndrome. Our results showed that delta-6 desaturase as well as elongase-6 expressions were upregulated in 3-month-old Zucker fatty rats as compared to lean littermates, inde…
Recent advances on stearoyl-Coa desaturase regulation in fatty liver diseases.
Stearoyl-CoA desaturase 1 (SCD-1) is a delta-9 fatty acid desaturase that catalyzes the synthesis of monounsaturated fatty acids. Indeed, SCD-1 is the critical control point regulating hepatic lipogenesis and lipid oxidation. Due to its central role in lipid metabolism in the liver, recent studies have focused on the involvement of SCD-1 in the development of fatty liver during obesity, diabetes mellitus, hypertension, excessive alcohol consumption, and in subjects with high triglyceride blood concentrations. The accumulation of fat in liver cells can be a sign that harmful conditions are developing, possibly associated with or leading to inflammation of the liver. This review evaluates the…
Effect of ethanol on polyunsaturated fatty acid biosynthesis in hepatocytes from spontaneously hypertensive rats.
Background: Polyunsaturated fatty acids (PUFA) play a major role in membrane structures that are modified during alcoholism. PUFA are also precursors of second messengers—eicosanoids—involved in the regulation of blood pressure. Alcohol has been related to hypertension and to alterations in liver PUFA metabolism. We investigated the effects of ethanol on PUFA biogenesis in hepatocytes of Wistar Kyoto (WKY) rats and Spontaneously Hypertensive Rats (SHR). The effects of a diet enriched with n-3 PUFA, which is known to modulate hypertension, were also studied. Methods: Isolated hepatocytes from male normotensive Wistar Kyoto (WKY) rats and SHR were incubated for 60 min in the presence of label…