Pharmacological effects of mTORC1/C2 inhibitor in a preclinical model of NASH progression
Knowledge of the benefits of mTOR inhibition concerning adipogenesis and inflammation has recently encouraged the investigation of a new generation of mTOR inhibitors for non-alcoholic steatohepatitis (NASH). We investigated whether treatment with a specific mTORC1/C2 inhibitor (Ku-0063794; KU) exer...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-11-01
|
| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223012453 |
| _version_ | 1797660553514057728 |
|---|---|
| author | Mahak Arora Zuzana Pavlíková Tomáš Kučera Petr Kozlík Tijana Šopin Tomáš Vacík Matej Ľupták Matthias Duda Ondřej Slanař Nikolina Kutinová Canová |
| author_facet | Mahak Arora Zuzana Pavlíková Tomáš Kučera Petr Kozlík Tijana Šopin Tomáš Vacík Matej Ľupták Matthias Duda Ondřej Slanař Nikolina Kutinová Canová |
| author_sort | Mahak Arora |
| collection | DOAJ |
| description | Knowledge of the benefits of mTOR inhibition concerning adipogenesis and inflammation has recently encouraged the investigation of a new generation of mTOR inhibitors for non-alcoholic steatohepatitis (NASH). We investigated whether treatment with a specific mTORC1/C2 inhibitor (Ku-0063794; KU) exerted any beneficial impacts on experimentally-induced NASH in vitro and in vivo. The results indicated that KU decreases palmitic acid-induced lipotoxicity in cultivated primary hepatocytes, thus emerging as a successful candidate for testing in an in vivo NASH dietary model, which adopted the intraperitoneal KU dosing route rather than oral application due to its significantly greater bioavailability in mice. The pharmacodynamics experiments commenced with the feeding of male C57BL/6 mice with a high-fat atherogenic western-type diet (WD) for differing intervals over several weeks aimed at inducing various phases of NASH. In addition to the WD, the mice were treated with KU for 3 weeks or 4 months. Acute and chronic KU treatments were observed to be safe at the given concentrations with no toxicity indications in the mice. KU was found to alleviate NASH-related hepatotoxicity, mitochondrial and oxidative stress, and decrease the liver triglyceride content and TNF-α mRNA in at least one set of in vivo experiments. The KU modulated liver expression of selected metabolic and oxidative stress-related genes depended upon the length and severity of the disease. Although KU failed to completely reverse the histological progression of NASH in the mice, we demonstrated the complexity of mTORC1/C2 signaling regulation and suggest a stratified therapeutic management approach throughout the disease course. |
| first_indexed | 2024-03-11T18:31:34Z |
| format | Article |
| id | doaj.art-155f833bc26f46b99ec51d7c9017b2ac |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-11T18:31:34Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-155f833bc26f46b99ec51d7c9017b2ac2023-10-13T11:02:39ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-11-01167115447Pharmacological effects of mTORC1/C2 inhibitor in a preclinical model of NASH progressionMahak Arora0Zuzana Pavlíková1Tomáš Kučera2Petr Kozlík3Tijana Šopin4Tomáš Vacík5Matej Ľupták6Matthias Duda7Ondřej Slanař8Nikolina Kutinová Canová9Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech RepublicInstitute of Histology and Embryology, First Faculty of Medicine, Charles University, Prague, Czech Republic; Department of Anthropology and Human Genetics, Faculty of Science, Charles University, Prague, Czech RepublicInstitute of Histology and Embryology, First Faculty of Medicine, Charles University, Prague, Czech RepublicDepartment of Analytical Chemistry, Faculty of Science, Charles University, Prague, Czech RepublicInstitute of Biology and Medical Genetics of the First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech RepublicInstitute of Biology and Medical Genetics of the First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech RepublicInstitute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech RepublicInstitute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech RepublicInstitute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech RepublicInstitute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; Correspondence to: Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Albertov 4, 128 00 Prague 2, Czech Republic.Knowledge of the benefits of mTOR inhibition concerning adipogenesis and inflammation has recently encouraged the investigation of a new generation of mTOR inhibitors for non-alcoholic steatohepatitis (NASH). We investigated whether treatment with a specific mTORC1/C2 inhibitor (Ku-0063794; KU) exerted any beneficial impacts on experimentally-induced NASH in vitro and in vivo. The results indicated that KU decreases palmitic acid-induced lipotoxicity in cultivated primary hepatocytes, thus emerging as a successful candidate for testing in an in vivo NASH dietary model, which adopted the intraperitoneal KU dosing route rather than oral application due to its significantly greater bioavailability in mice. The pharmacodynamics experiments commenced with the feeding of male C57BL/6 mice with a high-fat atherogenic western-type diet (WD) for differing intervals over several weeks aimed at inducing various phases of NASH. In addition to the WD, the mice were treated with KU for 3 weeks or 4 months. Acute and chronic KU treatments were observed to be safe at the given concentrations with no toxicity indications in the mice. KU was found to alleviate NASH-related hepatotoxicity, mitochondrial and oxidative stress, and decrease the liver triglyceride content and TNF-α mRNA in at least one set of in vivo experiments. The KU modulated liver expression of selected metabolic and oxidative stress-related genes depended upon the length and severity of the disease. Although KU failed to completely reverse the histological progression of NASH in the mice, we demonstrated the complexity of mTORC1/C2 signaling regulation and suggest a stratified therapeutic management approach throughout the disease course.http://www.sciencedirect.com/science/article/pii/S0753332223012453Ku-0063794atherogenic dietlipotoxicitymTORnon-alcoholic steatohepatitismouse |
| spellingShingle | Mahak Arora Zuzana Pavlíková Tomáš Kučera Petr Kozlík Tijana Šopin Tomáš Vacík Matej Ľupták Matthias Duda Ondřej Slanař Nikolina Kutinová Canová Pharmacological effects of mTORC1/C2 inhibitor in a preclinical model of NASH progression Biomedicine & Pharmacotherapy Ku-0063794 atherogenic diet lipotoxicity mTOR non-alcoholic steatohepatitis mouse |
| title | Pharmacological effects of mTORC1/C2 inhibitor in a preclinical model of NASH progression |
| title_full | Pharmacological effects of mTORC1/C2 inhibitor in a preclinical model of NASH progression |
| title_fullStr | Pharmacological effects of mTORC1/C2 inhibitor in a preclinical model of NASH progression |
| title_full_unstemmed | Pharmacological effects of mTORC1/C2 inhibitor in a preclinical model of NASH progression |
| title_short | Pharmacological effects of mTORC1/C2 inhibitor in a preclinical model of NASH progression |
| title_sort | pharmacological effects of mtorc1 c2 inhibitor in a preclinical model of nash progression |
| topic | Ku-0063794 atherogenic diet lipotoxicity mTOR non-alcoholic steatohepatitis mouse |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223012453 |
| work_keys_str_mv | AT mahakarora pharmacologicaleffectsofmtorc1c2inhibitorinapreclinicalmodelofnashprogression AT zuzanapavlikova pharmacologicaleffectsofmtorc1c2inhibitorinapreclinicalmodelofnashprogression AT tomaskucera pharmacologicaleffectsofmtorc1c2inhibitorinapreclinicalmodelofnashprogression AT petrkozlik pharmacologicaleffectsofmtorc1c2inhibitorinapreclinicalmodelofnashprogression AT tijanasopin pharmacologicaleffectsofmtorc1c2inhibitorinapreclinicalmodelofnashprogression AT tomasvacik pharmacologicaleffectsofmtorc1c2inhibitorinapreclinicalmodelofnashprogression AT matejluptak pharmacologicaleffectsofmtorc1c2inhibitorinapreclinicalmodelofnashprogression AT matthiasduda pharmacologicaleffectsofmtorc1c2inhibitorinapreclinicalmodelofnashprogression AT ondrejslanar pharmacologicaleffectsofmtorc1c2inhibitorinapreclinicalmodelofnashprogression AT nikolinakutinovacanova pharmacologicaleffectsofmtorc1c2inhibitorinapreclinicalmodelofnashprogression |