Effectiveness and safety of the SREBP1/2 inhibitor, fatostatin, in a preclinical model of metabolic dysfunction-associated steatotic liver disease progression

Kód výsledku v 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>

Nalezeny alternativní kódy

RIV/00216208:11110/25:10500292 RIV/00216208:11310/25:10500292

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Effectiveness and safety of the SREBP1/2 inhibitor, fatostatin, in a preclinical model of metabolic dysfunction-associated steatotic liver disease progression

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Effectiveness and safety of the SREBP1/2 inhibitor, fatostatin, in a preclinical model of metabolic dysfunction-associated steatotic liver disease progression

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/EF18_046%2F0016045" target="_blank" >EF18_046/0016045: Modernizace národní infrastruktury pro biologické a medicínské zobrazování Czech-BioImaging</a><br>

Návaznosti

V - Vyzkumna aktivita podporovana z jinych verejnych zdroju

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

European Journal of Pharmacology

ISSN

0014-2999

e-ISSN

1879-0712

Svazek periodika

1003

Číslo periodika v rámci svazku

September

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

17

Strana od-do

177890

Kód UT WoS článku

001539142000001

EID výsledku v databázi Scopus

2-s2.0-105010470336