LDT409（全过氧化物酶体增殖物激活受体部分激动剂）可减轻高果糖喂养小鼠代谢功能障碍相关的脂肪性肝病。
LDT409 (pan-PPAR partial agonist) mitigates metabolic dysfunction-associated steatotic liver disease in high-fructose-fed mice.
机构信息
Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
Graduate Program in Pharmaceutical Sciences, Department of Pharmacy, Health Sciences Faculty, University of Brasília, Brasília, DF, Brazil; Laboratory of Development of Therapeutic Innovations (LDT), Center for Tropical Medicine, Faculty of Medicine, University of Brasília, Brasília, DF, Brazil.
出版信息
Mol Cell Endocrinol. 2024 Dec 1;594:112380. doi: 10.1016/j.mce.2024.112380. Epub 2024 Sep 26.
AIM
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
LDT409 may represent a potential low-cost approach to treat metabolic dysfunction-associated steatotic liver disease, which does not currently have a specific treatment.
目的
本研究旨在评估 LDT409（一种源自腰果加工主要工业废物的全 PPAR 部分激动剂）对肝重构的影响，重点关注高果糖喂养小鼠的能量代谢和内质网（ER）应激。
方法
雄性 C57BL/6 小鼠接受对照饮食（C）或高果糖饮食（HFRU）十周。然后开始为期五周的治疗：C、C-LDT409、HFRU 和 HFRU-LDT409。LDT409（40mg/kg 体重）与饮食混合。
结果
HFRU 饮食导致胰岛素抵抗和内质网（ER）应激。高 Pparg 和低 Ppara 表达增加了 HFRU 喂养小鼠肝脏中的脂肪变性和促纤维化基因表达。受 PPAR-γ 调控的脂肪生成因子受到抑制，并减轻 ER 应激，同时伴随着由 PPAR-α 介导的β氧化增加，这是 LDT409 的有益作用。
结论
LDT409 可能代表一种治疗代谢功能障碍相关脂肪性肝病的潜在低成本方法，目前尚无特定治疗方法。
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