Lipidomics investigations into the tissue phospholipidomic landscape of invasive ductal carcinoma of the breast

Identification of tissue phospholipid alternations associated with invasive ductal carcinoma of breast.

Abstract 228: FADS2 Regulates Cardiometabolic Risk Phenotypes in Mice

Single nucleotide polymorphisms of the FADS2 gene associate with cardiometabolic risk in humans. Additionally, serum fatty acid profiles reflecting hepatic hyperactivity of the FADS2 gene product, delta-6 desaturase (D6D), correspond to cardiometabolic syndrome (CMS) phenotypes in humans and animal models. D6D catalyzes rate-limiting steps in essential polyunsaturated fatty acid (PUFA) metabolism, but its role in the pathogenesis of CMS has not been defined. In the present study, we employed pharmacological and genetic gain- and loss-of-function approaches to investigate the links between D6D activity and CMS phenotypes in mice. Transgenic overexpression (TG) of FADS2 in normal (FVB) mice modestly increases hepatic D6D protein expression and serum PUFA product/precursor ratios reflecting greater enzyme activity in vivo . FADS2 TG mice develop a mild, but progressive obesity and insulin resistance with age compared to WT mice, as well as elevated serum triglycerides and LDL/HDL and hepatic macrophage infiltration, but not hepatic steatosis. Global FADS2 ablation prevents obesity/insulin resistance and hyperlipidemia induced by high-fat feeding in C57Bl/6J mice, but promotes severe hepatic steatosis. Pharmacological D6D inhibition in vivo with SC-26196 (100 mpk 4-8 weeks) ameliorates hepatic inflammation and glucose intolerance in FADS2 TG mice and leptin-deficient ( ob ) mice, and prevents severe hyperlipidemia and atherosclerosis in ldlr -/- mice fed an atherogenic diet; despite augmenting hepatic steatosis in all cases. Tissue phospholipid analyses across these models revealed consistent positive relationships between D6D activity, pro-inflammatory eicosanoid accumulation, and a higher phosphatdiylcholine/phosphatidylethanolamine (PC/PE) ratio previously linked to increased hepatic VLDL synthesis and release. These studies establish an important role of D6D activity in the development of CMS and inflammation, and reveal novels links with tissue phospholipid class distribution and metabolism relevant to the development an atherogenic serum lipid profile, hepatic lipid homeostasis, and perhaps other aspects of cardiovascular risk currently under investigation in our laboratory.

Modifications induced by dietary lipid source in adipose tissue phospholipid fatty acids and their consequences in lipid mobilization

The aim of the present work was to assess the influence of dietary lipid source on fatty acid phospholipid profiles and on lipid mobilization. Forty male Wistar rats were divided into four groups and fed on high-fat diets which provided olive oil, sunflower oil, palm oil or beef tallow. All rats received the same amount of energy to avoid hyperphagia and differences in energy intake among groups. Phospholipid fatty acids were determined by GC. Lipolysis was stimulated in subcutaneous and perirenal isolated adipocytes by several lipolytic agents, and assessed by the determination of released glycerol. After 4 weeks of feeding, differences in body and adipose tissue weights were not observed. Dietary regimens caused great changes in adipose tissue phospholipid composition: rats fed on palm oil and beef tallow had higher concentrations of saturated fatty acids and animals fed on olive oil or sunflower oil had greater amounts of oleic and linoleic acids, respectively. These modifications did not lead to important changes in adipocyte lipolysis. Significant differences were only observed between palm-oil- and beef-tallow-fed groups when lipolysis was stimulated by isoproterenol in subcutaneous adipocytes. The fact that our feeding protocol did not induce differences in fat accumulation among groups avoids misinterpretations due to adiposity changes. The differences observed between both saturated-fat-fed groups, therefore, should only be attributable to dietary lipids. Despite this effect, the data from this work indicate that some diet-induced changes in adipose tissue fatty acid composition may have little effect on overall function.