Stankova 2023 MiP2023
Effect of telmisartan on nutritionally induced nonalcoholic steatohepatitis in mice. |
Link: MiP2023 Obergurgl AT
Stankova Pavla (2023)
Event: MiP2023 Obergurgl AT
Authors: Stankova Pavla, Peterova E, Dusek J, Elkalaf Moustafa, Cervinkova Zuzana, Kucera Otto
Introduction: In our previous study in a murine model of nonalcoholic steatohepatitis (NASH), we found reduced succinate-activated hepatic mitochondrial respiration and accumulation of succinate, a proinflammatory, profibrogenic, and oncogenic metabolite [1]. According to preliminary studies, telmisartan, an angiotensin II type 1 receptor blocker, positively affects insulin resistance and liver steatosis. This project aimed to investigate the effect of telmisartan on NASH in mice.
Methods: The NASH was induced in male mice fed a western-style diet (WD) for 36 weeks. During the last 6 weeks of the experiments, mice were administered daily telmisartan (oral gavage, 5 mg/kg b.w./day). Liver and epididymal fat histological changes were evaluated (Hematoxylin-eosin, Sirius red). Body parameters, plasma liver profile (VetScan), hepatic triglycerides, cholesterol, and the expression of selected proteins (WB/ELISA) and genes (qRT-PCR) were assessed. Mitochondrial respiration of liver homogenates was measured by high-resolution respirometry (OROBOROS Oxygraph-2k). Using Reporter Gene assay, telmisartan's activation of nuclear receptors was evaluated on HepG2 cells.
Results and discussion: Administration of telmisartan to mice fed a WD reduced absolute and relative liver weight and visceral adipose tissue weight, activities of ALT and AST, liver steatosis, and inflammation grade. These effects were accompanied by a significant increase in succinate-activated respiration in the ET state and the activity of succinate dehydrogenase. We confirmed that telmisartan is a PPAR-γ partial agonist and described the activating effect of telmisartan on the CAR receptor for the first time. Telmisartan appears to be a promising safety drug for treating NASH that affects metabolism at multiple levels.
- Staňková P, Kučera O, Peterová E, Elkalaf M, Rychtrmoc D, Melek J, Podhola M, Zubáňová V, Červinková Z (2021) Western Diet Decreases the Liver Mitochondrial Oxidative Flux of Succinate: Insight from a Murine NAFLD Model. https://doi.org/10.3390/ijms22136908
• Keywords: NASH, Telmisartan, Succinate dehydrogenase, PPAR-γ, CAR
• O2k-Network Lab: CZ Hradec Kralove Cervinkova Z
Affiliations and acknowledgements
- Stankova Pavla1, Peterova E1,2, Dusek J1, Elkalaf M1, Cervinkova Z1, Kucera O1
- Dept of Physiology, Fac of Medicine in Hradec Kralove, Charles Univ, Czech Republic
- Dept of Medical Biochemistry, Fac of Medicine in Hradec Kralove, Charles Univ, Czech Republic
- Corresponding author: stankovap@lfhk.cuni.cz
- Stankova Pavla1, Peterova E1,2, Dusek J1, Elkalaf M1, Cervinkova Z1, Kucera O1
- Funding: This work was supported by InoMed project CZ.02.1.01/0.0/0.0/18_069/0010046 co-funded by the EU.
Labels:
Organism: Mouse
Tissue;cell: Liver
Preparation: Homogenate
HRR: Oxygraph-2k
Event: Oral