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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.

Background— Remodeling of myocardial phospholipids has been reported in various forms of heart failure for decades, but the mechanism and pathophysiological relevance of this phenomenon have remained unclear. We examined the hypothesis that δ-6 desaturase (D6D), the rate-limiting enzyme in long-chain polyunsaturated fatty acid biosynthesis, mediates the signature pattern of fatty acid redistribution observed in myocardial phospholipids after chronic pressure overload and explored plausible links between this process and disease pathogenesis. Methods and Results— Compositional analysis of phospholipids from hearts explanted from patients with dilated cardiomyopathy revealed elevated polyunsaturated fatty acid product/precursor ratios reflective of D6D hyperactivity, manifesting primarily as lower levels of linoleic acid with reciprocally higher levels of arachidonic and docosahexaenoic acids. This pattern of remodeling was attenuated in failing hearts chronically unloaded with a left ventricular assist device. Chronic inhibition of D6D in vivo reversed similar patterns of myocardial polyunsaturated fatty acid redistribution in rat models of pressure overload and hypertensive heart disease and significantly attenuated cardiac hypertrophy, fibrosis, and contractile dysfunction in both models. D6D inhibition also attenuated myocardial elevations in pathogenic eicosanoid species, lipid peroxidation, and extracellular receptor kinase 1/2 activation; normalized cardiolipin composition in mitochondria; reduced circulating levels of inflammatory cytokines; and elicited model-specific effects on cardiac mitochondrial respiratory efficiency, nuclear factor κ B activation, and caspase activities. Conclusions— These studies demonstrate a pivotal role of essential fatty acid metabolism in myocardial phospholipid remodeling induced by hemodynamic stress and reveal novel links between this phenomenon and the propagation of multiple pathogenic systems involved in maladaptive cardiac remodeling and contractile dysfunction.

Aims Cardiolipin (CL) is a tetra-acyl phospholipid that provides structural and functional support to several proteins in the inner mitochondrial membrane. The majority of CL in the healthy mammalian heart contains four linoleic acid acyl chains (L4CL). A selective loss of L4CL is associated with mitochondrial dysfunction and heart failure in humans and animal models. We examined whether supplementing the diet with linoleic acid would preserve cardiac L4CL and attenuate mitochondrial dysfunction and contractile failure in rats with hypertensive heart failure. Methods and results Male spontaneously hypertensive heart failure rats (21 months of age) were administered diets supplemented with high-linoleate safflower oil (HLSO) or lard (10% w/w; 28% kilocalorie fat) or without supplemental fat (control) for 4 weeks. HLSO preserved L4CL and total CL to 90% of non-failing levels (vs. 61–75% in control and lard groups), and attenuated 17–22% decreases in state 3 mitochondrial respiration observed in the control and lard groups ( P < 0.05). Left ventricular fractional shortening was significantly higher in HLSO vs. control (33 ± 2 vs. 29 ± 2%, P < 0.05), while plasma insulin levels were lower (5.4 ± 1.1 vs. 9.1 ± 2.3 ng/mL; P < 0.05), with no significant effect of lard supplementation. HLSO also increased serum concentrations of several eicosanoid species compared with control and lard diets, but had no effect on plasma glucose or blood pressure. Conclusion Moderate consumption of HLSO preserves CL and mitochondrial function in the failing heart and may be a useful adjuvant therapy for this condition.

Peroxisome proliferator activated receptor-alpha (PPARa) is a lipogenic transcription factor known to exert pleiotropic effects in the cardiovascular system by mechanisms that are incompletely unde...