Effectiveness and safety of the SREBP1/2 inhibitor, fatostatin, in a preclinical model of metabolic dysfunction-associated steatotic liver disease progression
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064165%3A_____%2F25%3A10500292" target="_blank" >RIV/00064165:_____/25:10500292 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11110/25:10500292 RIV/00216208:11310/25:10500292
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=QqkHEvFv4r" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=QqkHEvFv4r</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.ejphar.2025.177890" target="_blank" >10.1016/j.ejphar.2025.177890</a>
Alternative languages
Result language
angličtina
Original language name
Effectiveness and safety of the SREBP1/2 inhibitor, fatostatin, in a preclinical model of metabolic dysfunction-associated steatotic liver disease progression
Original language description
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver disorder that can progress to metabolic dysfunction-associated steatohepatitis (MASH), potentially leading to liver fibrosis, cirrhosis, and cancer. As there is no sufficient specific pharmacological treatment for the progression of MASLD to MASH, we focused on the study of master transcriptional regulators involved in energy, cholesterol and lipid metabolism and adipogenesis. Therefore, our experimental work aimed to investigate the possible hepatoprotective effects and safety of fatostatin, which is the inhibitor of sterol regulatory element binding proteins 1 and 2 (SREBP1/2), in preclinical dietary models of the MASLD progression. Pretreatment of primary hepatocytes with fatostatin improved in vitro lipotoxicity produced by palmitic acid. To induce MASLD-to-MASH progression in vivo, male C57BL6J mice received a special western-type atherogenic diet with fructose and glucose in drinking water for 12 weeks. Despite the simultaneous administration of the diet to mice, an additional 4-week fatostatin treatment significantly improved the oral glucose tolerance test and reduced body, adipose tissue and liver weights, fasting glycemia, alkaline phosphatase, total cholesterol, liver conjugated dienes, nitrites and triglycerides, steatosis, and histopathological total MASLD activity score. These effects were related to the beneficial modulatory effect of fatostatin on liver expression of genes involved in lipid metabolism. Although fatostatin remarkably slowed the progression of MASLD, it produced elevated serum TNF-alpha, representing systemic inflammation, and severe skin adverse reactions similar to eczema, previously not reported. Therefore, we assume that liver-targeted specific inhibition of SREBP1/2 could be valuable in treating the progression of MASLD to MASH without concomitant skin toxicity.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30104 - Pharmacology and pharmacy
Result continuities
Project
<a href="/en/project/EF18_046%2F0016045" target="_blank" >EF18_046/0016045: Modernization of the National Infrastructure for Biological and Medical Imaging Czech-BioImaging</a><br>
Continuities
V - Vyzkumna aktivita podporovana z jinych verejnych zdroju
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
European Journal of Pharmacology
ISSN
0014-2999
e-ISSN
1879-0712
Volume of the periodical
1003
Issue of the periodical within the volume
September
Country of publishing house
NL - THE KINGDOM OF THE NETHERLANDS
Number of pages
17
Pages from-to
177890
UT code for WoS article
001539142000001
EID of the result in the Scopus database
2-s2.0-105010470336