SUMMARY Mice deficient in the nuclear hormone receptor RORγt have defective development of thymocytes, lymphoid organs, Th17 cells and type 3 innate lymphoid cells. RORγt binds to oxysterols derived from cholesterol catabolism but it is not clear whether these are its natural ligands. Here, we show that sterol lipids are necessary and sufficient to drive RORγt-dependent transcription. We combined overexpression, RNA interference and genetic deletion of metabolic enzymes to study RORγ-dependent transcription. Our results are consistent with the RORγt ligand(s) being a cholesterol biosynthetic intermediate (CBI) downstream of lanosterol and upstream of zymosterol. Analysis of lipids bound to RORγ identified molecules with molecular weights consistent with CBIs. Furthermore, CBIs stabilized the RORγ ligand-binding domain and induced co-activator recruitment. Genetic deletion of metabolic enzymes upstream of the RORγt-ligand(s) affected the development of lymph nodes and Th17 cells. Our data suggest that CBIs play a role in lymphocyte development potentially through regulation of RORγt.

Obesity with associated comorbidities is currently a worldwide epidemic and among the most challenging health conditions in the 21st century. A major metabolic consequence of obesity is insulin resistance which underlies the pathogenesis of the metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of obesity and metabolic syndrome. It comprises a disease spectrum ranging from simple steatosis (fatty liver), through nonalcoholic steatohepatitis (NASH) to fibrosis, and ultimately liver cirrhosis. Abnormality in lipid and lipoprotein metabolism accompanied by chronic inflammation is the central pathway for the development of metabolic syndrome-related diseases, such as atherosclerosis, cardiovascular disease (CVD), and NAFLD. This paper focuses on pathogenic aspect of lipid and lipoprotein metabolism in NAFLD and the relevant mouse models of this complex multifactorial disease.

The present review describes the transgenic mouse models that have been designed to evaluate the functions of the cytochrome P450s involved in cholesterol and bile acid synthesis, as well as their link with disease. The knockout of cholesterogenic Cyp51 is embrionally lethal, with symptoms of Antley–Bixler syndrome occurring in mice, whereas the evidence for this association is conflicting in humans. Disruption of Cyp7a1 from classic bile acid synthesis in mice leads to either increased postnatal death or a milder phenotype with elevated serum cholesterol. The latter is similar to the case in humans, where CYP7A1 mutations associate with high plasma low‐density lipoprotein and hepatic cholesterol content, as well as deficient bile acid excretion. Disruption of Cyp8b1 from an alternative bile acid pathway results in the absence of cholic acid and a reduced absorption of dietary lipids; however, the human CYP8B1 polymorphism fails to explain differences in bile acid composition. Unexpectedly, apparently normal Cyp27a1−/− mice still synthesize bile acids that originate from the compensatory pathway. In humans, CYP27A1 mutations cause cerebrotendinous xanthomatosis, suggesting that only mice can compensate for the loss of alternative bile acid synthesis. In line with this, Cyp7b1 knockouts are also apparently normal, whereas human CYP7B1 mutations lead to a congenital bile acid synthesis defect in children or spastic paraplegia in adults. Mouse knockouts of the brain‐specific Cyp46a1 have reduced brain cholesterol excretion, whereas, in humans, CYP46A1 polymorphisms associate with cognitive impairment. At present, cytochrome P450 family 39 is poorly characterized. Despite important physiological differences between humans and mice, mouse models prove to be an invaluable tool for understanding the multifactorial facets of cholesterol and bile acid‐related disorders.

This study examined the effects on healthy adults of a new emotional self-management program, consisting of two key techniques, "Cut-Thru" and the "Heart Lock-In." These techniques are designed to eliminate negative thought loops and promote sustained positive emotional states. The hypotheses were that training and practice in these techniques would yield lowered levels of stress and negative emotion and cortisol, while resulting in increased positive emotion and DHEA levels over a one-month period. In addition, we hypothesized that increased coherence in heart rate variability patterns would be observed during the practice of the techniques. Forty-five healthy adults participated in the study, fifteen of whom acted as a comparison group for the psychological measures. Salivary DHEA/DHEAS and cortisol levels were measured, autonomic nervous system function was assessed by heart rate variability analysis, and emotions were measured using a psychological questionnaire. Individuals in the experimental group were assessed before and four weeks after receiving training in the self-management techniques. The experimental group experienced significant increases in the positive affect scales of Caring and Vigor and significant decreases in the negative affect scales of Guilt, Hostility, Burnout, Anxiety and Stress Effects, while no significant changes were seen in the comparison group. There was a mean 23 percent reduction in cortisol and a 100 percent increase in DHEA/DHEAS in the experimental group. DHEA was significantly and positively related to the affective state Warmheartedness, whereas cortisol was significantly and positively related to Stress Effects. Increased coherence in heart rate variability patterns was measured in 80 percent of the experimental group during the use of the techniques. The results suggest that techniques designed to eliminate negative thought loops can have important positive effects on stress, emotions and key physiological systems. The implications are that relatively inexpensive interventions may dramatically and positively impact individuals' health and well-being. Thus, individuals may have greater control over their minds, bodies and health than previously suspected.

This review provides an overview of lipids and lipid metabolism in relation to COVID-19, with special attention on cholesterol. Cholesterol enriched lipid rafts represent a platform for viruses to enter the host cell by endocytosis. Generally, higher membrane cholesterol coincides with higher efficiency of COVID-19 entry. Inversely, patients with COVID-19 show lowered levels of blood cholesterol, high-density and low-density lipoproteins. The modulated efficiency of viral entry can be explained by availability of SR-B1 and LDL-receptors. Especially HDL seems to have a variety of roles, from being itself a scavenger for viruses, an immune modulator and mediator of viral entry. Due to inverse roles of membrane cholesterol and lipoprotein cholesterol in COVID-19 infected patients, treatment of these patients with cholesterol lowering statins remains controversial. In conclusion, cholesterol and lipoproteins are potential markers for monitoring the viral infection status where mechanistic inconsistencies warrant immediate further research.