Novel PPARα agonist MHY553 alleviates hepatic steatosis by increasing fatty acid oxidation and decreasing inflammation during aging.
Novel PPARα agonist MHY553 alleviates hepatic steatosis by increasing fatty acid oxidation and decreasing inflammation during aging.
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DOI：
10.18632/oncotarget.17695
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发表时间：
2017-07-11
期刊：
影响因子：
--
通讯作者：
Chung HY
中科院分区：
文献类型：
--
作者：
Kim SM;Lee B;An HJ;Kim DH;Park KC;Noh SG;Chung KW;Lee EK;Kim KM;Kim DH;Kim SJ;Chun P;Lee HJ;Moon HR;Chung HY
肝脏脂肪变性常见于肥胖和老年人。由于肝脂肪变性与代谢综合征密切相关，包括胰岛素抵抗、血脂异常和炎症，因此已经做出了许多努力来开发改善它的化合物。开发了（苯并[d]噻唑-2-基）苯-1，3-二醇（MHY 553），并使用年轻和老年Sprague-Dawley大鼠和HepG 2细胞研究其对肝脂肪变性的有益作用。对接模拟和Western blotting证实，MHY 553处理可增加PPARα的活性，但不增加其它亚型的活性。当口服给药时，MHY 553显著改善了衰老诱导的肝脂肪变性，而体重和肝损伤标志物的血清水平没有变化。与体内结果一致，MHY 553抑制肝X受体激动剂在HepG 2细胞中诱导的甘油三酯积累。关于潜在机制，MHY 553刺激PPARα易位到细胞核中，并增加其下游脂肪酸氧化相关基因（包括CPT-1A和ACOX 1）的mRNA水平，而脂肪生成信号转导无明显变化。此外，MHY 553显著抑制老年大鼠中的炎症mRNA表达。总之，MHY 553是一种新型的PPARα激动剂，部分通过增加β-氧化信号和减少肝脏炎症来改善衰老诱导的肝脏脂肪变性。MHY 553是一种潜在的治疗衰老性肝脂肪变性的药物。
Hepatic steatosis is frequently observed in obese and aged individuals. Because hepatic steatosis is closely associated with metabolic syndromes, including insulin resistance, dyslipidemia, and inflammation, numerous efforts have been made to develop compounds that ameliorate it. Here, a novel peroxisome proliferator-activated receptor (PPAR) α agonist, 4-(benzo[d]thiazol-2-yl)benzene-1,3-diol (MHY553) was developed, and investigated its beneficial effects on hepatic steatosis using young and old Sprague-Dawley rats and HepG2 cells. Docking simulation and Western blotting confirmed that the activity of PPARα, but not that of the other PPAR subtypes, was increased by MHY553 treatment. When administered orally, MHY553 markedly ameliorated aging-induced hepatic steatosis without changes in body weight and serum levels of liver injury markers. Consistent with in vivo results, MHY553 inhibited triglyceride accumulation induced by a liver X receptor agonist in HepG2 cells. Regarding underlying mechanisms, MHY553 stimulated PPARα translocation into the nucleus and increased mRNA levels of its downstream genes related to fatty acid oxidation, including CPT-1A and ACOX1, without apparent change in lipogenesis signaling. Furthermore, MHY553 significantly suppresses inflammatory mRNA expression in old rats. In conclusion, MHY553 is a novel PPARα agonist that improved aged-induced hepatic steatosis, in part by increasing β-oxidation signaling and decreasing inflammation in the liver. MHY553 is a potential pharmaceutical agent for treating hepatic steatosis in aging.
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DOI：
10.1093/gerona/glr124
发表时间：
2011-11-01
影响因子：
5.1
作者：
Kuhla, Angela;Blei, Tina;Vollmar, Brigitte
通讯作者：
Vollmar, Brigitte
人类脂肪肝病：旧问题和新见解。
DOI：
10.1126/science.1204265
发表时间：
2011-06-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cohen JC;Horton JD;Hobbs HH
通讯作者：
Hobbs HH
影响因子：
4.3
作者：
Bertolotti, Marco;Lonardo, Amedeo;Loria, Paola
通讯作者：
Loria, Paola
影响因子：
64.8
作者：
ISSEMANN, I;GREEN, S
通讯作者：
GREEN, S
影响因子：
3.3
作者：
Jay, Mollie A.;Ren, Jun
通讯作者：
Ren, Jun