Thyroid hormone receptor alpha modulates fibrogenesis in hepatic stellate cells

Objective: Progressive hepatic fibrosis can be considered the final stage of chronic liver disease. Hepatic stellate cells (HSC) play a central role in liver fibrogenesis. Thyroid hormones (TH, e.g. thyroxine; T4 and triiodothyronine; T3) significantly affect development, growth, cell differentiation and metabolism through activation of TH receptor α and/or β (TRα/β). Here, we evaluated the influence of TH in hepatic fibrogenesis. Design: Human liver tissue was obtained from explanted livers following transplantation. TRα-deficient (TRα-KO) and wild-type (WT) mice were fed a control or a profibrogenic methionine-choline deficient (MCD) diet. Liver tissue was assessed by qRT-PCR for fibrogenic gene expression. In vitro, HSC were treated with TGFβ in the presence or absence of T3. HSC with stable TRα knockdown and TRα deficient mouse embryonic fibroblasts (MEF) were used to determine receptor-specific function. Activation of HSC and MEF was assessed using the wound healing assay, Western blotting, and qRT-PCR. Results: TRα and TRβ expression is downregulated in the liver during hepatic fibrogenesis in humans and mice. TRα represents the dominant isoform in HSC. In vitro, T3 blunted TGFβ-induced expression of fibrogenic genes in HSC and abrogated wound healing by modulating TGFβ signalling, which depended on TRα presence. In vivo, TRα-KO enhanced MCD diet-induced liver fibrogenesis. Conclusion: These observations indicate that TH action in non-parenchymal cells is highly relevant. The interaction of TRα with TH regulates the phenotype of HSC via the TGFβ signalling pathway. Thus, the TH–TR axis may be a valuable target for future therapy of liver fibrosis.</p

Hypoglykämie durch paraneoplastische Sekretion von Insulin-like Growth Factor-I (IGF-I) bei einer Patientin mit metastasiertem großzelligen Bronchialkarzinom

Erster Fall einer bisher nicht bekannten Pathogenese hypoglykämischer Episoden bei einer Patientin durch Insulin-like-growth-factor I im Unterschied zur klassischen IGF-II-vermittelten Tumor-Hypoglykämie. Bestimmung von Glukose, Insulin, C-Peptid, freiem und Gesamt-IGF-I, -II, IGF-Bindungsproteinen (spezifische Immunoassays). Molekulargewicht von IGF-I: Gelchromatographie bei saurem pH. Zuordnung von IGF-I, IGF-II zu Bindungsproteinen: neutrale Sephadex-Gelfiltration. Immunzytochemie für IGF-I in einer Lymphknotenmetastase. Hypoglykämien mit supprimiertem Insulin, C-Peptid, Proinsulin. Hohe Konzentration von Gesamt-IGF-I, freiem IGF-I. Gleiches Molekulargewicht von IGF-I im Vergleich zu Gesunden mit gleicher Aufteilung von IGF-I,-II, der Bindungsproteine 2 und 3 in binäre/ ternäre Komplexe. Gesamt, freies, big-IGF-II normal. Lymphknoten mit großzelligem Karzinom und Nachweis von IGF-I. Therapie mit Wachstumshormon und Prednisolon ohne Hypoglykämien bei gleichen IGF-I-Konzentrationen

The influence of sampling time on indirect reference limits, decision limits, and the estimation of biological variation of random plasma glucose concentrations

Objectives: Plasma glucose concentrations exhibit a pronounced daytime-dependent variation. The oscillations responsible for this are currently not considered in the determination of reference limits (RL) and decision limits. Methods: We characterized the daily variation inherent in large-scale laboratory data from two different university hospitals (site 1 n=513,682, site 2 n=204,001). Continuous and distinct RL for daytime and night were estimated. Diurnal characteristics of glucose concentrations were further investigated by quantile regression analyses introducing age and cosinor-functions as predictors in the model. Results: Diurnal variations expressed as amplitude/Midline Estimating Statistic of Rhythm (MESOR) ratio, averaged 7.7% (range 5.9-9.3%). The amplitude of glucose levels decreased with increasing concentrations. Between 06:00 and 10:00 h an average decrease of 4% has to be considered. Nocturnal glucose samples accounted for only 5% of the total amount but contributed to 19.5% of all findings over 11.1 mmol/L. Partitioning of RL between day and night is merely justified for the upper reference limit. The nocturnal upper RLs for both genders differed from those obtained during the day by 11.0 and 10.6% at site 1 and by 7.6 and 7.5% at site 2. Conclusions: We conclude that indirect approaches to estimate upper RL of random plasma glucose concentrations require stratification concerning the time of sample collection

A Potential Role for Bile Acid Signaling in Celiac Disease-Associated Fatty Liver

Celiac disease (CeD) is a chronic autoimmune disorder characterized by an intolerance to storage proteins of many grains. CeD is frequently associated with liver damage and steatosis. Bile acid (BA) signaling has been identified as an important mediator in gut–liver interaction and the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here, we aimed to analyze BA signaling and liver injury in CeD patients. Therefore, we analyzed data of 20 CeD patients on a gluten-free diet compared to 20 healthy controls (HC). We furthermore analyzed transaminase levels, markers of cell death, BA, and fatty acid metabolism. Hepatic steatosis was determined via transient elastography, by MRI and non-invasive scores. In CeD, we observed an increase of the apoptosis marker M30 and more hepatic steatosis as compared to HC. Fibroblast growth factor 19 (FGF19) was repressed in CeD, while low levels were associated with steatosis, especially in patients with high levels of anti-tissue transglutaminase antibodies (anti-tTG). When comparing anti-tTG-positive CeD patients to individuals without detectable anti-tTG levels, hepatic steatosis was accentuated. CeD patients with significant sonographic steatosis (defined by CAP ≥ 283 db/m) were exclusively anti-tTG-positive. In summary, our results suggest that even in CeD patients in clinical remission under gluten-free diet, alterations in gut–liver axis, especially BA signaling, might contribute to steatotic liver injury and should be further addressed in future studies and clinical practice

Anti-TNFα treatment in Crohn’s disease:Impact on hepatic steatosis, gut-derived hormones and metabolic status

Background and Aims An association between Crohn's disease (CD) and hepatic steatosis has been reported. However, the underlying mechanisms of steatosis progression in CD are not clear. Among the most effective CD treatments are agents that inhibit Tumor-Necrosis-Factor (TNF) activity, yet it is unclear why anti-TNF alpha agents would affect steatosis in CD. Recent studies suggest that microbiome can affect both, CD and steatosis pathogenesis. Therefore, we here analysed a potential relationship between anti-TNF treatment and hepatic steatosis in CD, focusing on the gut-liver axis. Methods This cross-sectional study evaluated patients with established CD, with and without anti-TNF alpha treatment, analysing serum markers of liver injury, measurement of transient elastography, controlled attenuation parameter (CAP) and MRI for fat detection. Changes in lipid and metabolic profiles were assessed by serum and stool lipidomics and metabolimics. Additionally, we analysed gut microbiota composition and mediators of bile acid (BA) signalling via stool and serum analysis. Results Patients on anti-TNF alpha treatment had less hepatic steatosis as assessed by CAP and MRI. Serum FGF19 levels were significantly higher in patients on anti-TNF alpha therapy and associate with reduced steatosis and increased bowel motility. Neutral lipids including triglycerides were reduced in the serum of patients on anti-TNF treatment. Bacteria involved in BA metabolism and FGF19 regulation, including Firmicutes, showed group-specific alterations with low levels in patients without anti-TNF alpha treatment. Low abundance of Firmicutes was associated with higher triglyceride levels. Conclusions Anti-TNF alpha treatment is associated with reduced steatosis, lower triglyceride levels, alterations in FXR-signalling (eg FGF19) and microbiota composition in CD.PM is supported by the German Research Foundation/Deutsche Foschungsgemeinschaft-(MA-6864/1-1) and the European Association for the Study of the Liver (EASL). SS received funding from the EASL and the German Liver Foundation (Deutsche Leberstiftung). AL is supported by the funds of the European Commission through the 'European funds for regional development' (EFRE) as well as by the regional Ministry of Economy, Science, and Digitalization as part of the Autonomie im Alter research group. FJC received funding from MINECO Retos (SAF2016-78711), EXOHEP-CM (S2017/BMD-3727), NanoLiver (CM Y2018/NMT-4949), ERAB (Ref. EA 18/14), AMMF (2018/117), UCM (25-2019), COST Action (CA17112), RYC (2014-15242) and Gilead Liver Research 2018. AC is supported by the Wilhelm-Laupitz-Foundation. LPB is supported by the German Research Foundation/Deutsche Foschungsgemeinschaft (BE-3967/3-1) and the Dr Werner Jackstaedt-Foundation

Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health&nbsp;disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithiums possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P &lt; 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10-12, R2 = 1.9%) and continuous (P = 6.4 × 10-9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10-4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment

Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li + PGS ) in patients with BD. To gain further insights into lithium’s possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li + PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi + Gen: N = 2367) and replicated in the combined PsyCourse ( N = 89) and BipoLife ( N = 102) studies. The associations of Li + PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P &lt; 0.05. Li + PGS was positively associated with lithium treatment response in the ConLi + Gen cohort, in both the categorical ( P = 9.8 × 10 − 12 , R 2 = 1.9%) and continuous ( P = 6.4 × 10 − 9 , R 2 = 2.6%) outcomes. Compared to bipolar patients in the 1 st decile of the risk distribution, individuals in the 10 th decile had 3.47-fold (95%CI: 2.22–5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome ( P = 3.9 × 10 − 4 , R 2 = 0.9%), but not for the continuous outcome ( P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li + PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment