The E3 ubiquitin ligase inducible degrader of the LDL receptor/myosin light chain interacting protein in health and disease

PURPOSE OF REVIEW: The RING E3 ubiquitin ligase inducible degrader of the LDL receptor (IDOL, also known as MYLIP) promotes ubiquitylation and subsequent lysosomal degradation of the LDL receptor (LDLR), thus acting to limit uptake of lipoprotein-derived cholesterol into cells. Next to the LDLR, IDOL also promotes degradation of two related receptors, the very LDL receptor (VLDLR) and apolipoprotein E receptor 2 (APOER2), which have important signaling functions in the brain. We review here the emerging role of IDOL in lipoprotein and energy metabolism, neurodegenerative diseases, and the potential for therapeutic targeting of IDOL. RECENT FINDINGS: Genetic studies suggest an association between IDOL and lipoprotein metabolism in humans. Studies in rodents and nonhuman primates support an in-vivo role for IDOL in lipoprotein metabolism, and also uncovered an unexpected role in whole-body energy metabolism. Recent evaluation of IDOL function in the brain revealed a role in memory formation and progression of Alzheimer's disease. The report of the first IDOL inhibitor may facilitate further investigations on therapeutic strategies to target IDOL. SUMMARY: IDOL is emerging as an important determinant of lipid and energy metabolism in metabolic disease as well as in Alzheimer's disease. IDOL targeting may be beneficial in treating these conditions

Het delen van mantelzorg: wat zijn de overwegingen?

Due to social, political, and demographic developments in Dutch healthcare, the pressure on informal carers of vulnerable, senior citizens living at home continues to increase. To relieve this pressure, people in the senior citizens’ social network are looking for ways to share care tasks with others. However, many informal caregivers seem to experience a threshold in this respect. This pilot study focuses on understanding the considerations involved in sharing caregiving tasks with others. Therefore, semi-structured interviews were conducted with six informal caregivers of single, senior citizens living at home. This study shows that these considerations are characterised by a relationship between informal caregivers’ workload, their shyness to ask others for help, and the perception of care recipients’ demand, combined with informal caregivers’ natural inclination to do it themselves. Feelings of being responsible for the care and behaviour of care recipients, and the choices that must be made for them seem to play an additional role. To develop adequate solutions that lead to sharing informal care with others, and relieving the pressure on informal caregivers, more insight into the (personal) mechanisms behind this sense of responsibility seems necessary

Regulation of intestinal LDLR by the LXR-IDOL axis

Background and aims: Cholesterol metabolism is tightly regulated by transcriptional and post-transcriptional mechanisms. Accordingly, dysregulation of cholesterol metabolism is a major risk factor for the development of coronary artery disease and associated complications. In recent years, it has become apparent that next to the liver, the intestine plays a key role in systemic cholesterol metabolism by governing cholesterol absorption, secretion, and incorporation into lipoprotein particles. We have previously demonstrated that the Liver X receptor (LXR)-regulated E3 ubiquitin ligase inducible degrader of LDLR (IDOL) is a regulator of cholesterol uptake owing to its ability to promote the ubiquitylation of the low-density lipoprotein receptor (LDLR). However, whether the LXR-IDOL-LDLR axis regulates the LDLR in the intestine and whether this influences intestinal cholesterol homeostasis is not known. Methods: In this study, we evaluated the role of the LXR-IDOL-LDLR axis in enterocyte cell models and in primary enterocytes isolated from Idol(−/−) and wild type mice. Furthermore, we studied the regulation of intestinal LDLR in Idol(−/−) and in wild type mice treated with the LXR agonist GW3965. Finally, we assessed ezetimibe-induced trans-intestinal cholesterol efflux in Idol(−/−) mice. Results: We show that in a wide range of intestinal cell lines LXR activation decreases LDLR protein abundance, cell surface occupancy, and LDL uptake in an IDOL-dependent manner. Similarly, we find that pharmacological dosing of C57BL6/N mice with the LXR agonist GW3965 increases Idol expression across the intestine with a concomitant reduction in Ldlr protein. Conversely, primary enterocytes isolated from Idol(−/−) mice have elevated Ldlr. To test whether these changes contribute to trans-intestinal cholesterol efflux, we measured fecal cholesterol in mice following ezetimibe dosing, but found no differences between Idol(−/−) and control mice in this setting. Conclusions: In conclusion, our study establishes that the LXR-IDOL-LDLR axis is active in the intestine and is part of the molecular circuitry that maintains cholesterol homeostasis in enterocytes

Cognitive behavioral therapy for misophonia: A randomized clinical trial

BACKGROUND: Patients with misophonia suffer from anger or disgust confronted with specific sounds such as smacking or breathing. Avoidance of cue-related situations results in social isolation and significant functional impairment. This is the first randomized, controlled cognitive behavioral therapy (CBT) trial for misophonia, evaluating the short- and long-term efficacy. METHODS: The evaluator-blinded, randomized clinical trial was conducted from May 2017 until December 2018 at an academic outpatient clinic. Misophonia patients were randomly assigned to 3 months of weekly group-CBT or a waiting list and tested at baseline, 3 months (following CBT or waiting list), 6 months (after cross-over), and 15/18 months (1-year follow-up). CBT consisted of task concentration and arousal reduction, positive affect labeling, and stimulus manipulation. Co-primary outcomes were symptom severity assessed by the Amsterdam Misophonia Scale-Revised (AMISOS-R) and improvement on the Clinical Global Impression-Improvement (CGI-I). Secondary outcomes were self-assessed ratings of general psychopathology (Symptom Checklist-90-Revised [SCL-90-R]) and quality of life (five-dimensional EuroQol [EQ5-D], Sheehan Disability Scale [SDS], WHO Quality of Life-BREF [WHOQoL-BREF]). RESULTS: In all, 54 out of 71 patients were included (mean age, 33.06 [SD, 14.13] years; 38 women [70.4%]) and 46 (85%) completed the study. In the randomized phase, CBT resulted in statistically significant less misophonia symptoms in the short-term (-9.7 AMISOS-R; 95% CI, -12.0 to -7.4; p < .001, d = 1.97). The CBT group had an observed clinical improvement (CGI-I < 3) in 37% compared to 0% in the waiting list group (p < .001). The effect of CBT was maintained at 1-year follow-up on primary and secondary outcomes. CONCLUSIONS: This first randomized control trial shows both short-term and long-term efficacy of CBT for misophonia

Adjuvanted vaccines in pregnancy:no evidence for effect of the adjuvanted H1N1/09 vaccination on occurrence of preeclampsia or intra-uterine growth restriction

OBJECTIVE: During the H1N1/09 pandemic, pregnant women in the Netherlands were vaccinated with an adjuvanted vaccine. During pregnancy, the maternal immune system changes to enable placental development and growth and acceptance of the semi-allogeneic fetus. As an adjuvant is a pro-inflammatory substance, it may interfere with these immunological changes, resulting in poor placentation or placental growth, which may result in preeclampsia (PE) and fetal intra-uterine growth restriction (IUGR). This study investigated a possible association between adjuvanted H1N1/09 vaccination and the development of PE and/or IUGR. STUDY DESIGN: Case-control study. Cases were Dutch women with PE and/or IUGR occurring during H1N1/09 vaccination program. Controls had uncomplicated pregnancies during the same period. Maternal characteristics, pregnancy and neonatal outcomes were collected from medical files. Participants were contacted by telephone to enquire about vaccination. Data were analyzed using t-tests, Chi-square tests or Fisher's exact tests. Multivariate analysis was conducted to control for confounders. RESULTS: We included 254 cases and 247 controls. Of the cases, 90 (35.4%) were vaccinated, compared to 87 (35.2%) of the controls (OR:1.009, 95% CI:0.70-1.46, p:0.961). The majority (73.5%) had been vaccinated in second and third trimester. In multivariate analysis, there were no confounders influencing these results. Exploratory subgroup analysis did not show an association between vaccination status in subgroups of women with either PE or IUGR. CONCLUSION: Our study showed no association between adjuvanted H1N1/09 vaccination and PE and/or IUGR

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Inactivation of the E3 Ubiquitin Ligase IDOL Attenuates Diet-Induced Obesity and Metabolic Dysfunction in Mice

Objective- The E3 ubiquitin ligase IDOL (inducible degrader of the LDLR [LDL (low-density lipoprotein) receptor]) is a post-transcriptional regulator of LDLR abundance. Model systems and human genetics support a role for IDOL in regulating circulating LDL levels. Whether IDOL plays a broader metabolic role and affects development of metabolic syndrome-associated comorbidities is unknown. Approach and Results- We studied WT (wild type) and Idol(-/-) (Idol-KO) mice in 2 models: physiological aging and diet-induced obesity. In both models, deletion of Idol protected mice from metabolic dysfunction. On a Western-type diet, Idol loss resulted in decreased circulating levels of cholesterol, triglycerides, glucose, and insulin. This was accompanied by protection from weight gain in short- and long-term dietary challenges, which could be attributed to reduced hepatosteatosis and fat mass in Idol-KO mice. Although feeding and intestinal fat uptake were unchanged in Idol-KO mice, their brown adipose tissue was protected from lipid accumulation and had elevated expression of UCP1 (uncoupling protein 1) and TH (tyrosine hydroxylase). Indirect calorimetry indicated a marked increase in locomotion and suggested a trend toward increased cumulative energy expenditure and fat oxidation. An increase in in vivo clearance of reconstituted lipoprotein particles in Idol-KO mice may sustain this energetic demand. In the BXD mouse genetic reference population, hepatic Idol expression correlates with multiple metabolic parameters, thus providing support for findings in the Idol-KO mice. Conclusions- Our study uncovers an unrecognized role for Idol in regulation of whole body metabolism in physiological aging and on a Western-type diet. These findings support Idol inhibition as a therapeutic strategy to target multiple metabolic syndrome-associated comorbidities

Pearson’s correlation between the sedative effect of ketamine and ketamine-induced performance impairment.

<p>The sedative effect of ketamine is measured as the sedation score, rated at the start of the task (ketamine minus placebo condition. It is quantified as the distance (in mm) from a mark placed by the subject on each scale (a 100 mm line connecting two opposite states of mind), measured from the left end of the scale (see ‘Methods’ for details). The ketamine-induced performance impairment is calculated as the average performance on the texture discrimination task (ketamine minus placebo condition). No significant correlation was observed.</p