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 M, Cervinkova Z, Kucera O

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-, CAR

• O2k-Network Lab: CZ Hradec Kralove Cervinkova Z

Labels:

Organism: Mouse Tissue;cell: Liver Preparation: Homogenate

HRR: Oxygraph-2k Event: E2

Affiliations and acknowledgements

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.