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

• 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
• ISSN: 0303-7207; 1872-8057; 1872-8057
• DOI: 10.1016/j.mce.2024.112380

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.