Choung Sorim, Joung Kyong Hye, You Bo Ram, Park Sang Ki, Kim Hyun Jin, Ku Bon Jeong
Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.
Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.
PPAR Res. 2018 Jun 13;2018:4292509. doi: 10.1155/2018/4292509. eCollection 2018.
Nonalcoholic fatty liver disease (NAFLD) is strongly associated with insulin resistance. The peroxisome proliferator-activated receptor (PPAR) activators, thiazolidinediones, (TZDs), are insulin sensitizers used as a treatment for NAFLD. However, TZDs are a controversial treatment for NAFLD because of conflicting results regarding hepatic steatosis and fibrosis. To evaluate a possible effective drug for treatment of NAFLD, we investigated the effects of a newly developed TZD, lobeglitazone, with an emphasis on hepatic lipid metabolism. Lobeglitazone treatment for 4 weeks in high fat diet- (HFD-) induced obese mice (HL group) improved insulin resistance and glucose intolerance compared to HFD-induced obese mice (HU group). The gene levels related to hepatic gluconeogenesis also decreased after treatment by lobeglitazone. The livers of mice in the HL group showed histologically reduced lipid accumulation, with lowered total plasma cholesterol and triglyceride levels. In addition, the HL group significantly decreased the hepatic expression of genes associated with lipid synthesis, cholesterol biosynthesis, and lipid droplet development and increased the hepatic expression of genes associated with fatty acid -oxidation, thus suggesting that lobeglitazone decreased hepatic steatosis and reversed hepatic lipid dysregulation. Livers with steatohepatitis contained increased levels of PPAR and phosphorylated PPAR at serine 273, leading to downregulation of expression of genes associated with insulin sensitivity. Notably, the treatment of lobeglitazone increased the protein levels of PPAR and diminished levels of PPAR phosphorylated at serine 273, which were increased by a HFD, suggesting that induction of PPAR and posttranslational modification of PPAR in livers by lobeglitazone might be an underlying mechanism of the improvement seen in NAFLD. Taken together, our data showed that lobeglitazone might be an effective treatment for NAFLD.
非酒精性脂肪性肝病（NAFLD）与胰岛素抵抗密切相关。过氧化物酶体增殖物激活受体（PPAR）激动剂噻唑烷二酮类（TZDs）是用于治疗NAFLD的胰岛素增敏剂。然而，由于在肝脂肪变性和纤维化方面存在相互矛盾的结果，TZDs治疗NAFLD存在争议。为了评估一种可能有效治疗NAFLD的药物，我们研究了一种新开发的TZDs罗格列酮的作用，重点关注肝脏脂质代谢。与高脂饮食诱导的肥胖小鼠（HU组）相比，高脂饮食（HFD）诱导的肥胖小鼠（HL组）接受罗格列酮治疗4周后，胰岛素抵抗和葡萄糖不耐受得到改善。罗格列酮治疗后，与肝脏糖异生相关的基因水平也降低。HL组小鼠的肝脏在组织学上显示脂质积累减少，血浆总胆固醇和甘油三酯水平降低。此外，HL组显著降低了与脂质合成、胆固醇生物合成和脂滴形成相关基因的肝脏表达，并增加了与脂肪酸氧化相关基因的肝脏表达，这表明罗格列酮减少了肝脏脂肪变性并逆转了肝脏脂质失调。患有脂肪性肝炎的肝脏中PPAR和丝氨酸273磷酸化的PPAR水平升高，导致与胰岛素敏感性相关基因的表达下调。值得注意的是，罗格列酮治疗增加了PPAR的蛋白水平，并降低了丝氨酸273磷酸化的PPAR水平，而高脂饮食会使其升高，这表明罗格列酮诱导肝脏中PPAR并对其进行翻译后修饰可能是NAFLD改善的潜在机制。综上所述，我们的数据表明罗格列酮可能是治疗NAFLD的有效药物。
