Coarse-grained simulations of branched bilayer membranes: effects of cholesterol-dependent phase separation on curvature-driven lipid sorting

Our recent coarse-grained (CG) molecular dynamics (MD) simulations of membranes with a hemifused-ribbon (λ-shaped) geometry showed curvature-driven demixing leading to enrich ment in dioleoyl-phosphatidylethanolamine (DOPE) in a negatively-curved region (at C = –0.8 nm–1) of a DOPE/dipalmitoyl-phosphati-dylcholine (DPPC) membrane. Here we extend the analysis with respect to lipid composition and simulation time. Simulations of 12 – 20 μs effective time show that, compared with DOPE of the DOPE/DPPC system, a DPPC/dilinoleyl-PC [di(18:2)PC] membrane showed a similar degree of enrichment of di(18:2)PC in the curved region with C=–0.8 nm–1. For the latter mixture, even weak negative curvatures (C=–0.5 – 0.6 nm–1) caused significant degrees of di(18:2)PC enrichment. In agreement with recent studies of a planar bilayer, a ternary DPPC/ di(18:2)PC/cholesterol 0.42:0.28:0.3 mixture phase-separated into nanoscale raft-like liquid-ordered (Lo) and non-raft liquid-disordered (Ld) phases on a sub-microsecond time scale. The Lo domains were preferentially localized at planar portions, whereas the Ld domains were positioned mainly in curved regions of the membrane. Unlike binary dioleoylphosphatidylcho-line (DOPC)/cholesterol and DPPC/cholesterol mixtures, which showed only a slight enrich ment of cholesterol in the curved region, the ternary mixtures showed considerable migra tion of cholesterol and DPPC from the curved to the planar region. A pronounced degree of lipid segregation due to the preferential distribution of the Ld and Lo domains in the curved and planar regions, respectively, was observed even when the curvature of the fused monolayers (originally ‘cis’ leaflets) was weakened (C= –0.5 nm-1). Overall, the results are consistent with theoretical predictions based on spontaneous curvature of the constituent lipids and the difference in rigidity between the Ld and Lo domains, whereas lipid-lipid interactions, such as PE-PE or DPPC-cholesterol, as well as propensity for interleaflet colocalization (registration) of the Lo and Ld domains appear to significantly amplify curvature-induced lipid demixing in the λ system. Intriguingly, for the DPPC/ di(18:2)PC/cholesterol ternary mixtures, a Lo/Ld domain boundary often moved to the branched point of the membrane, suggesting enhanced flexibility at the domain boundary. We hypothesize that curvature-driven lipid sorting and energetically favored localization of domain boundaries at sharp bends in the membranes may collaborate to assist intracellular lipid sorting.

Rapid Decrease and Subsequent Increase in the Serum Triglycerides Accompanied by CD36 Transcript Increase in an Acute Stress Mice Model

In this article, we report the changes in serum triglyceride (TG) levels that occurred during repeated tail blood sampling using a mouse restrainer. We used three groups of mice, namely, “PBS-restrained” “PBS-unrestrained” and “mock-restrained”. The mice in the PBS-restrained and PBS-unrestrained groups were intraperitoneally (i.p.) injected with 100 mL PBS and tail blood sampling was performed at 1, 5, 8, 24, and 48 h after i.p. injection. For the mock-restrained group, no i.p. injection was performed whereas the subsequent tail blood sampling was similarly performed. During the tail blood sampling, the mice of the two “restrained” groups were placed inside the restrainer designed from an open-ended 50 mL conical tube. The blood from the mice in the PBS-unrestrained group mice was sampled from the tail held by the operator’s hands while being allowed to move on a stage. Strikingly, in all of the three groups, the serum TG level initially decreased to remarkably low levels (approximately 30 mg/dL) after several blood samplings were performed over 8 h. This decrease was followed by a 2 - 3-fold increase in the levels relative to that in the control mice in the subsequent 24 - 48 h time period. We concluded that the acute stress associated with blood sampling caused alterations in TG levels. Serum levels of free fatty acid showed only modest changes. Changes in TG levels were not associated with serum corticosterone levels but with a dramatic increase in CD36 transcript levels in the liver. The relevance of this finding to the previously reported release of lipoprotein lipase (LPL) from white fatty tissue into the plasma during acute stress is also discussed.

Serum Uric Acid Level Has Stronger Correlations with Metabolic Syndrome-Related Markers in Women than in Men in a Japanese Health Check-Up Population

Background A serum uric acid (UA) level of 7.0 mg/dL has been used as the criterion for hyperuricemia in Japan regardless of gender, despite higher serum UA levels in men than in women. Serum UA has been identified as a predictive biomarker for metabolic syndrome (MetS);however, the gender differences in the association between UA levels and MetS-related conditions in a Japanese population have not been completely assessed. Objective To examine gender and age differences in the associations between serum UA levels and other biomarkers within a health-screened Japanese population and to evaluate the usefulness of serum UA as a predictor of MetS between the two genders. Methods A cross-sectional study of healthy individuals in Japan (16,391 men;16,656 women) was conducted. Associations between UA and several biomarkers were analyzed for each gender type and for age- and serum UA level-stratified groups. Logistic regression was used to analyze the association of age and serum UA levels with MetS-related conditions. Receiver operating characteristic (ROC) curve analysis was performed to identify the UA cut-off value for predicting the risk of the MetS-related conditions. Results Serum UA levels in women had stronger correlations with MetS-related biomarkers than in men. After adjusting for age, the odds ratios for a 1-mg/dL serum UA increase for diabetes mellitus and dyslipidemia in women were 1.13 (95% confidence interval, 1.04 - 1.23) and 1.30 (1.25 - 1.34), respectively. In ROC analysis, women had significantly higher area under the curve (AUC) values for MetS prediction than men. Conclusion An elevated serum UA level has a higher predictive ability for the risk of MetS-related conditions in Japanese women than in men. The optimal serum UA cut-off value for MetS in women was suggested to be approximately 5 mg/dL, remarkably lower than that in men.