Bio21 - Research Publications

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    Circulating Lipids Are Associated with Alcoholic Liver Cirrhosis and Represent Potential Biomarkers for Risk Assessment
    Meikle, PJ ; Mundra, PA ; Wong, G ; Rahman, K ; Huynh, K ; Barlow, CK ; Duly, AMP ; Haber, PS ; Whitfield, JB ; Seth, D ; Sookoian, SC (PUBLIC LIBRARY SCIENCE, 2015-06-24)
    Liver disease is the greatest cause of death related to alcohol and a major public health problem. While excessive alcohol intake results in hepatosteatosis in most individuals, this can progress in some to more severe forms of liver disease including fibrosis and cirrhosis. An ongoing challenge in the management of alcoholic liver disease is the identification of liver injury early in the disease process such that intervention strategies can prevent serious long term outcomes. Given that excessive alcohol consumption results in dysregulation of lipid metabolism we applied lipid profiling technology to characterise and compare serum lipid profiles from excessive chronic drinkers with no liver disease to those with advanced alcoholic cirrhosis. In a cohort of 59 excessive drinkers (31 with liver cirrhosis and 28 with no evidence of liver disease) we used electrospray ionisation tandem mass spectrometry to measure over 300 individual lipid species in serum, including species of the major phospholipid, sphingolipid, glycerolipid and sterol classes. Six of the 25 lipid classes and subclasses were significantly associated with alcoholic liver cirrhosis; these included dihexosylceramide, trihexosylceramide, alkylphosphatidylcholine, lysoalkylphosphatidylcholine, phosphatidylinositol and free cholesterol. Multivariate classification models created with only clinical characteristics gave an optimal model with an AUC of 0.847 and an accuracy of 79.7%. The addition of lipid measurements to the clinical characteristics resulted in models of improved performance with an AUC of 0.892 and accuracy of 81.8%. The gain in AUC and accuracy of the combined models highlight the potential of serum lipids as markers of liver injury in alcoholic liver disease.
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    Lipidomic Profiling of Murine Macrophages Treated with Fatty Acids of Varying Chain Length and Saturation Status
    Huynh, K ; Pernes, G ; Mellett, NA ; Meikle, PJ ; Murphy, AJ ; Lancaster, GI (MDPI, 2018-06)
    Macrophages are abundant within adipose tissue depots where they are exposed to fatty acids, leading to lipid accumulation. Herein, we have determined the effects of various fatty acids on the macrophage lipidome. Using targeted mass-spectrometry, we were able to detect 641 individual lipid species in primary murine macrophages treated with a variety of saturated fatty acids and an un-saturated fatty acid, either alone or in combination. The most pronounced effects were observed for the long-chain saturated fatty acid palmitate, which increased the total abundance of numerous classes of lipids. While other medium- and long-chain saturated fatty acids, as well as the long-chain unsaturated fatty acid, had less pronounced effects on the total abundance of specific lipid classes, all fatty acids induced marked alterations in the abundance of numerous lipid species within given lipid classes. Fatty acid treatment markedly altered overall phospholipid saturation status; these effects were most pronounced for phosphatidylcholine and ether-phosphatidylcholine lipid species. Finally, treatment of macrophages with either palmitate or stearate in combination with oleate prevented many of the changes that were observed in macrophages treated with palmitate or stearate alone. Collectively, our results reveal substantial and specific remodelling of the macrophage lipidome following treatment with fatty acids.
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    Development and variation of a ceramide- and phospholipid-based cardiovascular risk estimation score for coronary artery disease patients
    Hilvo, M ; Meikle, PJ ; Pedersen, ER ; Tell, GS ; Dhar, I ; Brenner, H ; Schoettker, B ; Laaperi, M ; Kauhanen, D ; Koistinen, KM ; Jylha, A ; Huynh, K ; Mellett, NA ; Tonkin, AM ; Sullivan, DR ; Simes, J ; Nestel, P ; Koenig, W ; Rothenbacher, D ; Nygard, O ; Laaksonen, R (OXFORD UNIV PRESS, 2020-01-14)
    AIMS: Distinct ceramide lipids have been shown to predict the risk for cardiovascular disease (CVD) events, especially cardiovascular death. As phospholipids have also been linked with CVD risk, we investigated whether the combination of ceramides with phosphatidylcholines (PCs) would be synergistic in the prediction of CVD events in patients with atherosclerotic coronary heart disease in three independent cohort studies. METHODS AND RESULTS: Ceramides and PCs were analysed using liquid chromatography-mass spectrometry (LC-MS) in three studies: WECAC (The Western Norway Coronary Angiography Cohort) (N = 3789), LIPID (Long-Term Intervention with Pravastatin in Ischaemic Disease) trial (N = 5991), and KAROLA (Langzeiterfolge der KARdiOLogischen Anschlussheilbehandlung) (N = 1023). A simple risk score, based on the ceramides and PCs showing the best prognostic features, was developed in the WECAC study and validated in the two other cohorts. This score was highly significant in predicting CVD mortality [multiadjusted hazard ratios (HRs; 95% confidence interval) per standard deviation were 1.44 (1.28-1.63) in WECAC, 1.47 (1.34-1.61) in the LIPID trial, and 1.69 (1.31-2.17) in KAROLA]. In addition, a combination of the risk score with high-sensitivity troponin T increased the HRs to 1.63 (1.44-1.85) and 2.04 (1.57-2.64) in WECAC and KAROLA cohorts, respectively. The C-statistics in WECAC for the risk score combined with sex and age was 0.76 for CVD death. The ceramide-phospholipid risk score showed comparable and synergistic predictive performance with previously published CVD risk models for secondary prevention. CONCLUSION: A simple ceramide- and phospholipid-based risk score can efficiently predict residual CVD event risk in patients with coronary artery disease.
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    High-coverage plasma lipidomics reveals novel sex-specific lipidomic fingerprints of age and BMI: Evidence from two large population cohort studies
    Beyene, HB ; Olshansky, G ; Smith, AAT ; Giles, C ; Huynh, K ; Cinel, M ; Mellett, NA ; Cadby, G ; Hung, J ; Hui, J ; Beilby, J ; Watts, GF ; Shaw, JS ; Moses, EK ; Magliano, DJ ; Meikle, PJ ; Locasale, JW (PUBLIC LIBRARY SCIENCE, 2020-09)
    Obesity and related metabolic diseases show clear sex-related differences. The growing burden of these diseases calls for better understanding of the age- and sex-related metabolic consequences. High-throughput lipidomic analyses of population-based cohorts offer an opportunity to identify disease-risk-associated biomarkers and to improve our understanding of lipid metabolism and biology at a population level. Here, we comprehensively examined the relationship between lipid classes/subclasses and molecular species with age, sex, and body mass index (BMI). Furthermore, we evaluated sex specificity in the association of the plasma lipidome with age and BMI. Some 747 targeted lipid measures, representing 706 molecular lipid species across 36 classes/subclasses, were measured using a high-performance liquid chromatography coupled mass spectrometer on a total of 10,339 participants from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), with 563 lipid species being validated externally on 4,207 participants of the Busselton Health Study (BHS). Heat maps were constructed to visualise the relative differences in lipidomic profile between men and women. Multivariable linear regression analyses, including sex-interaction terms, were performed to assess the associations of lipid species with cardiometabolic phenotypes. Associations with age and sex were found for 472 (66.9%) and 583 (82.6%) lipid species, respectively. We further demonstrated that age-associated lipidomic fingerprints differed by sex. Specific classes of ether-phospholipids and lysophospholipids (calculated as the sum composition of the species within the class) were inversely associated with age in men only. In analyses with women alone, higher triacylglycerol and lower lysoalkylphosphatidylcholine species were observed among postmenopausal women compared with premenopausal women. We also identified sex-specific associations of lipid species with obesity. Lysophospholipids were negatively associated with BMI in both sexes (with a larger effect size in men), whilst acylcarnitine species showed opposing associations based on sex (positive association in women and negative association in men). Finally, by utilising specific lipid ratios as a proxy for enzymatic activity, we identified stearoyl CoA desaturase (SCD-1), fatty acid desaturase 3 (FADS3), and plasmanylethanolamine Δ1-desaturase activities, as well as the sphingolipid metabolic pathway, as constituent perturbations of cardiometabolic phenotypes. Our analyses elucidate the effect of age and sex on lipid metabolism by offering a comprehensive view of the lipidomic profiles associated with common cardiometabolic risk factors. These findings have implications for age- and sex-dependent lipid metabolism in health and disease and suggest the need for sex stratification during lipid biomarker discovery, establishing biological reference intervals for assessment of disease risk.
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    Krill Oil Has Different Effects on the Plasma Lipidome Compared with Fish Oil Following 30 Days of Supplementation in Healthy Women: A Randomized Controlled and Crossover Study
    Sung, HH ; Sinclair, AJ ; Huynh, K ; Smith, AAT ; Mellett, NA ; Meikle, PJ ; Su, XQ (MDPI, 2020-09)
    This is a follow-up of our previous postprandial study and it focused on the plasma lipidomic responses to 30 days of krill oil (KO) versus fish oil (FO) supplementations in healthy women. Eleven women (aged 18-50 years) consumed KO or FO for 30 days in a randomized, cross-over study, with at least a four-week washout period between supplementations. The daily supplements provided 1.27 g/day of long-chain (LC) omega-3 polyunsaturated fatty acids (PUFA) from KO (containing 0.76 g eicosapentaenoic acid (EPA), 0.42 g docosahexaenoic acid (DHA)) and 1.44 g/day from FO (containing 0.79 g EPA, 0.47 g DHA). Fasting plasma samples at days 0, 15, and 30 were analyzed using gas chromatography and liquid chromatography electrospray ionisation-tandem mass spectrometry. KO resulted in a significantly greater relative area under the curve (relAUC) for plasma EPA after 30 days. Lipidomic analysis showed that 26 of 43 lipid molecular species had a significantly greater relAUC in the KO group, while 17/43 showed a significantly lower relAUC compared with the FO group. More than 38% of the lipids species which increased more following KO contained omega-3 PUFA, while where FO was greater than KO, only 12% contained omega-3 PUFA. These data show that KO and FO do not have equivalent effects on the plasma lipidome.
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    Exceptional human longevity is associated with a specific plasma phenotype of ether lipids
    Pradas, I ; Jove, M ; Huynh, K ; Puig, J ; Ingles, M ; Borras, C ; Vina, J ; Meikle, PJ ; Pamplona, R (ELSEVIER, 2019-02)
    A lipid profile resistant to oxidative damage is an inherent trait associated with animal lifespan. However, there is a lack of lipidomic studies on human longevity. Here we use mass spectrometry based technologies to detect and quantify 137 ether lipids to define a phenotype of healthy humans with exceptional lifespan. Ether lipids were chosen because of their antioxidant properties and ability to modulate oxidative stress. Our results demonstrate that a specific ether lipid signature can be obtained to define the centenarian state. This profile comprises higher level of alkyl forms derived from phosphatidylcholine with shorter number of carbon atoms and double bonds; and decreased content in alkenyl forms from phosphatidylethanolamine with longer chain length and higher double bonds. This compositional pattern suggests that ether lipids from centenarians are more resistant to lipid peroxidation, and that ether lipid signature expresses an optimized feature associated with exceptional human longevity. These results are in keeping with the free radical theory of aging.
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    Lipidomics Reveals a Tissue-Specific Fingerprint
    Pradas, I ; Huynh, K ; Cabre, R ; Ayala, V ; Meikle, PJ ; Jove, M ; Pamplona, R (FRONTIERS MEDIA SA, 2018-08-28)
    In biological systems lipids generate membranes and have a key role in cell signaling and energy storage. Therefore, there is a wide diversity of molecular lipid expressed at the compositional level in cell membranes and organelles, as well as in tissues, whose lipid distribution remains unclear. Here, we report a mass spectrometry study of lipid abundance across 7 rat tissues, detecting and quantifying 652 lipid molecular species from the glycerolipid, glycerophospholipid, fatty acyl, sphingolipid, sterol lipid and prenol lipid categories. Our results demonstrate that every tissue analyzed presents a specific lipid distribution and concentration. Thus, glycerophospholipids are the most abundant tissue lipid, they share a similar tissue distribution but differ in particular lipid species between tissues. Sphingolipids are more concentrated in the renal cortex and sterol lipids can be found mainly in both liver and kidney. Both types of white adipose tissue, visceral and subcutaneous, are rich in glycerolipids but differing the amount. Acylcarnitines are mainly in the skeletal muscle, gluteus and soleus, while heart presents higher levels of ubiquinone than other tissues. The present study demonstrates the existence of a rat tissue-specific fingerprint.
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    Sex and APOE ε4 genotype modify the Alzheimer's disease serum metabolome
    Arnold, M ; Nho, K ; Kueider-Paisley, A ; Massaro, T ; Huynh, K ; Brauner, B ; MahmoudianDehkordi, S ; Louie, G ; Moseley, MA ; Thompson, JW ; St John-Williams, L ; Tenenbaum, JD ; Blach, C ; Chang, R ; Brinton, RD ; Baillie, R ; Han, X ; Trojanowski, JQ ; Shaw, LM ; Martins, R ; Weiner, MW ; Trushina, E ; Toledo, JB ; Meikle, PJ ; Bennett, DA ; Krumsiek, J ; Doraiswamy, PM ; Saykin, AJ ; Kaddurah-Daouk, R ; Kastenmueller, G (NATURE PUBLISHING GROUP, 2020-03-02)
    Late-onset Alzheimer's disease (AD) can, in part, be considered a metabolic disease. Besides age, female sex and APOE ε4 genotype represent strong risk factors for AD that also give rise to large metabolic differences. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 139 serum metabolites in 1,517 individuals from the AD Neuroimaging Initiative with AD biomarkers. We observed substantial sex differences in effects of 15 metabolites with partially overlapping differences for APOE ε4 status groups. Several group-specific metabolic alterations were not observed in unstratified analyses using sex and APOE ε4 as covariates. Combined stratification revealed further subgroup-specific metabolic effects limited to APOE ε4+ females. The observed metabolic alterations suggest that females experience greater impairment of mitochondrial energy production than males. Dissecting metabolic heterogeneity in AD pathogenesis can therefore enable grading the biomedical relevance for specific pathways within specific subgroups, guiding the way to personalized medicine.