LDT409 (pan-PPAR partial agonist) mitigates metabolic dysfunction-associated steatotic liver disease in high-fructose-fed mice

This study sought to evaluate the effects of LDT409, a pan-PPAR partial agonist obtained from the main industrial waste from cashew nut processing, on hepatic remodeling, highlighting energy metabolism and endoplasmic reticulum (ER) stress in high-fructose-fed mice. Male C57BL/6 mice received a cont...

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Bibliographic Details
Published in:	Molecular and cellular endocrinology Vol. 594; p. 112380
Main Authors:	Fernandes-da-Silva, Aline, Santana-Oliveira, Daiana Araujo, Oliveira, Andressa S de, Ferreira, Thaís A.M., Monteiro, Natália Cipriano, Silva-Veiga, Flávia Maria, Martins, Fabiane Ferreira, Cummins, Carolyn L., Romeiro, Luiz Antonio Soares, Souza-Mello, Vanessa
Format:	Journal Article
Language:	English
Published:	Ireland Elsevier B.V 01-12-2024
Subjects:	ER stress Fructose LDT409 MASLD PPAR-Alpha PPAR-Gamma PPAR-Alpha ER stress PPAR-Gamma LDT409 MASLD Fructose PPAR-alpha PPAR-gamma
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Summary:	This study sought to evaluate the effects of LDT409, a pan-PPAR partial agonist obtained from the main industrial waste from cashew nut processing, on hepatic remodeling, highlighting energy metabolism and endoplasmic reticulum (ER) stress in high-fructose-fed mice. Male C57BL/6 mice received a control diet (C) or a high-fructose diet (HFRU) for ten weeks. Then, a five-week treatment started: C, C-LDT409, HFRU, and HFRU-LDT409. The LDT409 (40 mg/kg of body weight) was mixed with the diets. The HFRU diet caused insulin resistance and endoplasmic reticulum (ER) stress. High Pparg and decreased Ppara expression increased steatosis and pro-fibrogenic gene expression in livers of HFRU-fed mice. Suppressed lipogenic factors, orchestrated by PPAR-gamma, and mitigated ER stress concomitant with the increase in beta-oxidation driven by PPAR-alpha mediated the LDT409 beneficial effects. LDT409 may represent a potential low-cost approach to treat metabolic dysfunction-associated steatotic liver disease, which does not currently have a specific treatment. •High-fructose diet drove insulin resistance and hepatic steatosis, without overweight.•LDT409 (pan-PPAR partial agonist) reduced body mass and insulin resistance.•LDT409 mitigated hepatic steatosis through reduced lipogenic gene expression.•Treated mice exhibited reduced endoplasmic reticulum stress and fibrogenic markers.•LDT409 may represent a potential low-cost approach to treat hepatic steatosis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0303-7207 1872-8057 1872-8057
DOI:	10.1016/j.mce.2024.112380