A PPAR Pan Agonist, MHY2013 Alleviates Age-Related Hepatic Lipid Accumulation by Promoting Fatty Acid Oxidation and Suppressing Inflammation
A PPAR Pan Agonist, MHY2013 Alleviates Age-Related Hepatic Lipid Accumulation by Promoting Fatty Acid Oxidation and Suppressing Inflammation
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DOI：
10.1248/bpb.b17-00371
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发表时间：
2018-01-01
影响因子：
2
通讯作者：
Chung, Hae Young
中科院分区：
文献类型：
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作者：
An, Hye Jin;Lee, Bonggi;Chung, Hae Young
非酒精性脂肪性肝病（NAFLD）是常见的肥胖和老年人。过氧化物酶体增殖物激活受体（PPARs）在调节肝脏脂质蓄积中发挥作用，这是NAFLD发展的标志。已经显示，PPAR泛激动剂2-（4-（5，6-亚甲基二氧基苯并[d]噻唑-2-基）-2-甲基苯氧基）-2-甲基丙酸（MHY2013）在肥胖小鼠（db/db）模型中预防脂肪肝形成和胰岛素抵抗。然而，MHY 2013对老年模型的有益影响仍然未知。在这项研究中，我们研究了MHY2013是否减少老年SD大鼠的肝脏脂质蓄积。我们使用荧光素酶测定证实MHY2013增加HepG2细胞中的三种PPAR亚型的活性。当在老年SD大鼠中口服给药时，MHY2013显著降低肝脏甘油三酯水平，而体重没有变化。关于潜在机制，MHY2013增加了脂质氧化相关基因的mRNA水平，包括肉毒碱棕榈酰转移酶1（CPTI）和过氧化物酶体酰基辅酶A氧化酶1（ACOX1），而脂肪生成相关基因的mRNA表达没有明显变化。此外，MHY2013显著增加全身成纤维细胞生长因子21（FGF 21）和脂联素水平，并抑制肝脏中的炎症mRNA表达。总之，MHY2013部分通过上调β-氧化信号传导和抑制肝脏炎症来减轻与年龄相关的肝脏脂质积累。因此，MHY2013是治疗年龄相关性肝脏脂质蓄积的潜在药剂。
Nonalcoholic fatty liver disease (NAFLD) is frequently observed in obese and aged individuals. Peroxisome proliferator-activated receptors (PPARs) play a role in regulating hepatic lipid accumulation, a hallmark of NAFLD development. A PPAR pan agonist, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013) has been shown to prevent fatty liver formation and insulin resistance in obese mice (db/db) model. However, the beneficial effects of MHY2013 in aged model remain unknown. In this study, we investigated whether MHY2013 alleviates hepatic lipid accumulation in aged Sprague-Dawley (SD) rats. We confirmed that MHY2013 increased the activities of three PPAR subtypes in HepG2 cells using luciferase assay. When administered orally in aged SD rats, MHY2013 markedly decreased the hepatic triglyceride levels without changes in body weight. Regarding underlying mechanisms, MHY2013 increased the mRNA levels of lipid oxidation-related genes, including carnitine palmitoyltransferase 1 (CPTI) and peroxisomal acyl-CoA oxidase 1 (ACOX1), without apparent change in the mRNA expression of lipogenesis-related genes. Furthermore, MHY2013 significantly increased systemic fibroblast growth factor 21 (FGF21) and adiponectin levels and suppressed inflammatory mRNA expression in the liver. In conclusion, MHY2013 alleviated age-related hepatic lipid accumulation, in part by upregulating beta-oxidation signaling and suppressing inflammation in the liver. Therefore, MHY2013 is a potential pharmaceutical agent for treating age-related hepatic lipid accumulation.