TY  - JOUR
A1  - Hohenester, Simon
A1  - Kanitz, Veronika
A1  - Schiergens, Tobias
A1  - Einer, Claudia
A1  - Nagel, Jutta
A1  - Wimmer, Ralf
A1  - Reiter, Florian P.
A1  - Gerbes, Alexander L.
A1  - De Toni, Enrico N.
A1  - Bauer, Christian
A1  - Holdt, Lesca
A1  - Mayr, Doris
A1  - Rust, Christian
A1  - Schnurr, Max
A1  - Zischka, Hans
A1  - Geier, Andreas
A1  - Denk, Gerald
T1  - IL-18 but not IL-1 signaling is pivotal for the initiation of liver injury in murine non-alcoholic fatty liver disease
JF  - International Journal of Molecular Sciences
N2  - Non-alcoholic fatty liver disease (NAFLD) is rising in prevalence, and a better pathophysiologic understanding of the transition to its inflammatory phenotype (NASH) is key to the development of effective therapies. To evaluate the contribution of the NLRP3 inflammasome and its downstream effectors IL-1 and IL-18 in this process, we applied the true-to-life “American lifestyle-induced obesity syndrome” (ALiOS) diet mouse model. Development of obesity, fatty liver and liver damage was investigated in mice fed for 24 weeks according to the ALiOS protocol. Lipidomic changes in mouse livers were compared to human NAFLD samples. Receptor knockout mice for IL-1 and IL-18 were used to dissect the impact of downstream signals of inflammasome activity on the development of NAFLD. The ALiOS diet induced obesity and liver steatosis. The lipidomic changes closely mimicked changes in human NAFLD. A pro-inflammatory gene expression pattern in liver tissue and increased serum liver transaminases indicated early liver damage in the absence of histological evidence of NASH. Mechanistically, Il-18r\(^{−/−}\)- but not Il-1r\(^{−/−}\) mice were protected from early liver damage, possibly due to silencing of the pro-inflammatory gene expression pattern. Our study identified NLRP3 activation and IL-18R-dependent signaling as potential modulators of early liver damage in NAFLD, preceding development of histologic NASH.
KW  - NAFLD
KW  - Western diet
KW  - NLRP3
KW  - inflammasome
KW  - interleukin 1
KW  - interleukin 18
KW  - NASH
KW  - ALiOS
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285221
SN  - 1422-0067
VL  - 21
IS  - 22
ER  - 
TY  - JOUR
A1  - John, Katharina
A1  - Franck, Martin
A1  - Al Aoua, Sherin
A1  - Rau, Monika
A1  - Huber, Yvonne
A1  - Schattenberg, Joern M.
A1  - Geier, Andreas
A1  - Bahr, Matthias J.
A1  - Wedemeyer, Heiner
A1  - Schulze-Osthoff, Klaus
A1  - Bantel, Heike
T1  - Non-invasive detection of fibrotic NASH in NAFLD patients with low or intermediate FIB-4
JF  - Journal of Clinical Medicine
N2  - Background: Non-alcoholic steatohepatitis (NASH) and fibrosis are the main prognostic factors in non-alcoholic fatty liver disease (NAFLD). The FIB-4 score has been suggested as an initial test for the exclusion of progressed fibrosis. However, increasing evidence suggests that also NASH patients with earlier fibrosis stages are at risk of disease progression, emphasizing the need for improved non-invasive risk stratification. Methods: We evaluated whether the apoptosis biomarker M30 can identify patients with fibrotic NASH despite low or intermediate FIB-4 values. Serum M30 levels were assessed by ELISA, and FIB-4 was calculated in an exploration (n = 103) and validation (n = 100) cohort of patients with histologically confirmed NAFLD. Results: The majority of patients with low FIB-4 (cut-off value < 1.3) in the exploration cohort revealed increased M30 levels (>200 U/L) and more than 80% of them had NASH, mostly with fibrosis. NASH was also detected in all patients with intermediate FIB-4 (1.3 to 2.67) and elevated M30, from which ~80% showed fibrosis. Importantly, in the absence of elevated M30, most patients with FIB-4 < 1.3 and NASH showed also no fibrosis. Similar results were obtained in the validation cohort. Conclusions: The combination of FIB-4 with M30 enables a more reliable identification of patients at risk for progressed NAFLD and might, therefore, improve patient stratification.
KW  - apoptosis
KW  - biomarker
KW  - fibrosis
KW  - FIB-4
KW  - NAFLD
KW  - NASH
KW  - keratin-18
KW  - M30
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281824
SN  - 2077-0383
VL  - 11
IS  - 15
ER  - 
TY  - JOUR
A1  - Metzner, Valentin
A1  - Herzog, Gloria
A1  - Heckel, Tobias
A1  - Bischler, Thorsten
A1  - Hasinger, Julia
A1  - Otto, Christoph
A1  - Fassnacht, Martin
A1  - Geier, Andreas
A1  - Seyfried, Florian
A1  - Dischinger, Ulrich
T1  - Liraglutide + PYY\(_{3-36}\) combination therapy mimics effects of Roux-en-Y bypass on early NAFLD whilst lacking-behind in metabolic improvements
JF  - Journal of Clinical Medicine
N2  - Background: Treatment options for NAFLD are still limited. Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB), has been shown to improve metabolic and histologic markers of NAFLD. Glucagon-like-peptide-1 (GLP-1) analogues lead to improvements in phase 2 clinical trials. We directly compared the effects of RYGB with a treatment using liraglutide and/or peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\)) in a rat model for early NAFLD. Methods: Obese male Wistar rats (high-fat diet (HFD)-induced) were randomized into the following treatment groups: RYGB, sham-operation (sham), liraglutide (0.4 mg/kg/day), PYY\(_{3-36}\) (0.1 mg/kg/day), liraglutide+PYY\(_{3-36}\), and saline. After an observation period of 4 weeks, liver samples were histologically evaluated, ELISAs and RNA sequencing + RT-qPCRs were performed. Results: RYGB and liraglutide+PYY\(_{3-36}\) induced a similar body weight loss and, compared to sham/saline, marked histological improvements with significantly less steatosis. However, only RYGB induced significant metabolic improvements (e.g., adiponectin/leptin ratio 18.8 ± 11.8 vs. 2.4 ± 1.2 in liraglutide+PYY\(_{3-36}\)- or 1.4 ± 0.9 in sham-treated rats). Furthermore, RNA sequencing revealed a high number of differentially regulated genes in RYGB treated animals only. Conclusions: The combination therapy of liraglutide+PYY\(_{3-36}\) partly mimics the positive effects of RYGB on weight reduction and on hepatic steatosis, while its effects on metabolic function lack behind RYGB.
KW  - liraglutide
KW  - GLP-1
KW  - peptide tyrosine tyrosine (PYY)
KW  - peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\))
KW  - RYGB
KW  - gastric bypass
KW  - obesity
KW  - NASH
KW  - NAFLD
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-255244
SN  - 2077-0383
VL  - 11
IS  - 3
ER  - 
TY  - JOUR
A1  - Jahn, Daniel
A1  - Dorbath, Donata
A1  - Kircher, Stefan
A1  - Nier, Anika
A1  - Bergheim, Ina
A1  - Lenaerts, Kaatje
A1  - Hermanns, Heike M.
A1  - Geier, Andreas
T1  - Beneficial effects of vitamin D treatment in an obese mouse model of non-alcoholic steatohepatitis
JF  - Nutrients
N2  - Serum vitamin D levels negatively correlate with obesity and associated disorders such as non-alcoholic steatohepatitis (NASH). However, the mechanisms linking low vitamin D (VD) status to disease progression are not completely understood. In this study, we analyzed the effect of VD treatment on NASH in mice. C57BL6/J mice were fed a high-fat/high-sugar diet (HFSD) containing low amounts of VD for 16 weeks to induce obesity, NASH and liver fibrosis. The effects of preventive and interventional VD treatment were studied on the level of liver histology and hepatic/intestinal gene expression. Interestingly, preventive and to a lesser extent also interventional VD treatment resulted in improvements of liver histology. This included a significant decrease of steatosis, a trend towards lower non-alcoholic fatty liver disease (NAFLD) activity score and a slight non-significant decrease of fibrosis in the preventive treatment group. In line with these changes, preventive VD treatment reduced the hepatic expression of lipogenic, inflammatory and pro-fibrotic genes. Notably, these beneficial effects occurred in conjunction with a reduction of intestinal inflammation. Together, our observations suggest that timely initiation of VD supplementation (preventive vs. interventional) is a critical determinant of treatment outcome in NASH. In the applied animal model, the improvements of liver histology occurred in conjunction with reduced inflammation in the gut, suggesting a potential relevance of vitamin D as a therapeutic agent acting on the gut–liver axis.
KW  - vitamin D
KW  - obesity
KW  - NAFLD
KW  - NASH
KW  - inflammation
KW  - intestine
KW  - gut–liver axis
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177222
VL  - 11
IS  - 1
ER  -