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Background The lipidome is rapidly garnering interest in the field of psychiatry. Recent studies have implicated lipidomic changes across numerous psychiatric disorders, not least in MDD—there is growing evidence that the concentrations of several classes of lipids are altered in those diagnosed with MDD. However, for lipidomic abnormalities to be considered potential treatment targets for MDD (rather than secondary manifestations of the disease), a shared etiology between lipid concentrations and MDD risk must be demonstrated. Methods In a sample of 567 individuals from 37 extended pedigrees (average size 13.57 people, range = 3-80) plus 30 singletons, we used mass-spectrometry lipidomic measures to evaluate the genetic overlap between twenty-three biologically distinct lipid classes and a continuous index of lifetime MDD risk. Results We found that the lipid class with the largest endophenotype ranking value (ERV, a standardized parametric measure of pleiotropy) were ether-phosphodatidylcholines (alkylphosphatidylcholine, PC(O) and alkenylphosphatidylcholine, PC(P) subclasses). Furthermore, we examined the cluster structure of the twenty-five species within the top-ranked lipid class, and the relationship of those clusters with MDD risk. This analysis revealed that species containing arachidonic acid generally exhibited the greatest degree of genetic overlap with MDD. Discussion This study is the first to demonstrate a shared genetic etiology between MDD risk and ether-phosphatidylcholine species containing arachidonic acid, an omega-6 fatty acid that is a precursor to inflammatory mediators, such as prostaglandins. The study highlights the potential utility of the well-characterized linoleic/arachidonic acid inflammation pathway as a diagnostic marker and/or treatment target for MDD.

Transient receptor potential (TRP) proteins form a superfamily of cation channels that predominantly regulate the flux of Ca2+ ions across membranes in both excitable and non-excitable cells. While many TRP channels respond to a wide variety of chemical and physical stimuli, several TRP channels exhibit constitutive activity. A recent structural analysis of a “minimal subunit” TRPV1 construct, a prototypical ligand-activated TRP channel, elucidated a mechanism of channel activation by agonists through the dynamic nature of the outer pore region of the channel. Though homologous to TRPV1, TRPV2 shows constitutive activity in the absence of ligand; however the mechanism underlying this activity is elusive due to lack of high-resolution structures. To further understand the critical role of the outer pore region in activity of TRP channels, we have determined the structure of full-length TRPV2 at ∼4A resolution by direct-electron counting cryo electron microscopy (cryoEM). The structure of TRPV2 revealed that this constitutively active TRP channel features a wide flexible outer pore region in the absence of activator. The geometry of this region differs from that observed in “minimal subunit” TRPV1 and is likely favored by the presence of the turret domain in the full-length TRPV2 protein used for structure determination. In contrast, the orientation of the TRPV2 lower gate and ankyrin repeat domains favored that of agonist-activated TRPV1, suggesting some common properties of TRPV channel open conformations. We propose that these newly revealed structural features contribute to non-selective cation conductance, explaining constitutive activity of TRPV2 and other TRP family members involved in sensory perception and human disease.

Diabetic cardiomyopathy is characterised by diastolic dysfunction, oxidative stress, fibrosis, apoptosis and pathological cardiomyocyte hypertrophy. Phosphoinositide 3-kinase (PI3K)(p110α) is a cardioprotective kinase, but its role in the diabetic heart is unknown. The aim of this study was to assess whether PI3K(p110α) plays a critical role in the induction of diabetic cardiomyopathy, and whether increasing PI3K(p110α) activity in the heart can prevent the development of cardiac dysfunction in a setting of diabetes.Type 1 diabetes was induced with streptozotocin in adult male cardiac-specific transgenic mice with increased PI3K(p110α) activity (constitutively active PI3K [p110α], caPI3K] or decreased PI3K(p110α) activity (dominant-negative PI3K [p110α], dnPI3K) and non-transgenic (Ntg) mice for 12 weeks. Cardiac function, histological and molecular analyses were performed.Diabetic Ntg mice displayed diastolic dysfunction and increased cardiomyocyte size, expression of atrial and B-type natriuretic peptides (Anp, Bnp), fibrosis and apoptosis, as well as increased superoxide generation and increased protein kinase C β2 (PKCβ2), p22 ( phox ) and apoptosis signal-regulating kinase 1 (Ask1) expression. Diabetic dnPI3K mice displayed an exaggerated cardiomyopathy phenotype compared with diabetic Ntg mice. In contrast, diabetic caPI3K mice were protected against diastolic dysfunction, pathological cardiomyocyte hypertrophy, fibrosis and apoptosis. Protection in diabetic caPI3K mice was associated with attenuation of left ventricular superoxide generation, attenuated Anp, Bnp, PKCβ2, Ask1 and p22 ( phox ) expression, and elevated AKT. Further, in cardiomyocyte-like cells, increased PI3K(p110α) activity suppressed high glucose-induced superoxide generation and enhanced mitochondrial function.These results demonstrate that reduced PI3K activity accelerates the development of diabetic cardiomyopathy, and that enhanced PI3K(p110α) activity can prevent adverse cardiac remodelling and dysfunction in a setting of diabetes.

Nonalcoholic fatty liver disease (NAFLD) comprises fat-accumulating conditions within hepatocytes that can cause severe liver damage and metabolic comorbidities. Studies suggest that mitochondrial dysfunction contributes to its development and progression and that the hepatic lipidome changes extensively in obesity and in NAFLD. To gain insight into the relationship between lipid metabolism and disease progression through different stages of NAFLD, we performed lipidomic analysis of plasma and liver biopsy samples from obese patients with nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH) and from those without NAFLD. Congruent with earlier studies, hepatic lipid levels overall increased with NAFLD. Lipid species that differed with NAFLD severity were related to mitochondrial dysfunction; specifically, hepatic cardiolipin and ubiquinone accumulated in NAFL, and levels of acylcarnitine increased with NASH. We propose that increased levels of cardiolipin and ubiquinone may help to preserve mitochondrial function in early NAFLD, but that mitochondrial function eventually fails with progression to NASH, leading to increased acylcarnitine. We also found a negative association between hepatic odd-chain phosphatidylcholine and NAFLD, which may result from mitochondrial dysfunction-related impairment of branched-chain amino acid catabolism. Overall, these data suggest a close link between accumulation of specific hepatic lipid species, mitochondrial dysfunction, and the progression of NAFLD.