Structure of the PPARα and -γ Ligand Binding Domain in Complex with AZ 242; Ligand Selectivity and Agonist Activation in the PPAR Family

AbstractBackground: The peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors belonging to the nuclear receptor family. The roles of PPARα in fatty acid oxidation and PPARγ in adipocyte differentiation and lipid storage have been characterized extensively. PPARs are activated by fatty acids and eicosanoids and are also targets for antidyslipidemic drugs, but the molecular interactions governing ligand selectivity for specific subtypes are unclear due to the lack of a PPARα ligand binding domain structure.Results: We have solved the crystal structure of the PPARα ligand binding domain (LBD) in complex with the combined PPARα and -γ agonist AZ 242, a novel dihydro cinnamate derivative that is structurally different from thiazolidinediones. In addition, we present the crystal structure of the PPARγ_LBD/AZ 242 complex and provide a rationale for ligand selectivity toward the PPARα and -γ subtypes. Heteronuclear NMR data on PPARα in both the apo form and in complex with AZ 242 shows an overall stabilization of the LBD upon agonist binding. A comparison of the novel PPARα/AZ 242 complex with the PPARγ/AZ 242 complex and previously solved PPARγ structures reveals a conserved hydrogen bonding network between agonists and the AF2 helix.Conclusions: The complex of PPARα and PPARγ with the dual specificity agonist AZ 242 highlights the conserved interactions required for receptor activation. Together with the NMR data, this suggests a general model for ligand activation in the PPAR family. A comparison of the ligand binding sites reveals a molecular explanation for subtype selectivity and provides a basis for rational drug design

Lack of association of MRI determined subclinical cardiovascular disease with dizziness and vertigo in a cross-sectional population-based study

OBJECTIVE We investigated the association between subclinical cardiovascular diseases assessed by MRI examination and symptoms of dizziness and vertigo in participants of a population-based sample. METHODS Data from 400 participants (169 women) aged from 39 to 73 of a cross-sectional MRI sub-study of the \dqKooperative Gesundheitsforschung in der Region Augsburg\dq (KORA) FF4 study from the south of Germany was used. MRI determined subclinical cardiovascular diseases include left and right ventricular structure and function as well as the presence of carotid plaque and carotid wall thickness. Cerebrum diseases include white matter lesions (WML) and cerebral microbleeds (CMB). The main outcomes of dizziness and vertigo were assessed by standardized interview. Logistic regression models were applied and adjusted odds ratios (OR) with 95% confidence intervals (CI) were provided. RESULTS Lifetime and 12-month prevalence of dizziness and vertigo were 30% (95%CI 26% to 35%) and 21% (95%CI 17% to 26%) respectively in this sample. On multivariable analysis, cardiac and carotid measurements were not associated with dizziness and vertigo excluding orthostatic vertigo (20%, 95CI 16% to 24%). Only in male participants, there was a significant association between WML and the presence of dizziness and vertigo (OR = 2.95, 95%CI 1.08 to 8.07). There was no significant association of CMB with dizziness and vertigo. However, CMB and WML were tending to associate with a higher risk of dizziness and vertigo in the whole sample (CMB: OR = 1.48, 95%CI 0.70; 3.15; WML: OR = 1.71, 95%CI 0.80 to 3.67;), in persons with prediabetes and diabetes (WML: OR = 2.71, 95%CI 0.89 to 8.23) and in men with normal glucose metabolism (CMB: OR = 2.60, 95%CI 0.56 to 12.0; WML: OR = 3.08, 95%CI 0.58 to 16.5). CONCLUSIONS In this sample of participants without manifest cardiovascular diseases, subclinical left and right ventricular function and carotid structure were consistently not associated with dizziness and vertigo. Subclinical cerebrum measurements, however, tend to increase the risk for dizziness and vertigo, especially in men and in persons with prediabetes or diabetes

Changes in mode of travel to work: a natural experimental study of new transport infrastructure

Background: New transport infrastructure may promote a shift towards active travel, thereby improving population health. The purpose of this study was to determine the effect of a major transport infrastructure project on commuters' mode of travel, trip frequency and distance travelled to work. Methods: Quasi-experimental analysis nested within a cohort study of 470 adults working in Cambridge, UK. The intervention consisted of the opening of a guided busway with a path for walking and cycling in 2011. Exposure to the intervention was defined as the negative of the square root of the shortest distance from home to busway. The outcome measures were changes in commute mode share and number of commute trips - both based on a seven-day travel-to-work record collected before (2009) and after (2012) the intervention - and change in objective commute distance. The mode share outcomes were changes in the proportions of trips (i) involving any active travel, (ii) involving any public transport, and (iii) made entirely by car. Separate multinomial regression models were estimated adjusting for commute and sociodemographic characteristics, residential settlement size and life events. Results: Proximity to the busway predicted an increased likelihood of a large (>30 %) increase in the share of commute trips involving any active travel (relative risk ratio [RRR] 1.80, 95 % CI 1.27, 2.55) and a large decrease in the share of trips made entirely by car (RRR 2.09, 95 % CI 1.35, 3.21), as well as a lower likelihood of a small (<30 %) reduction in the share of trips involving any active travel (RRR 0.47, 95 % CI 0.28, 0.81). It was not associated with changes in the share of commute trips involving any public transport, the number of commute trips, or commute distance. Conclusions: The new infrastructure promoted an increase in the share of commuting trips involving active travel and a decrease in the share made entirely by car. Further analysis will show the extent to which the changes in commute mode share were translated into an increase in time spent in active commuting and consequent health gain