Kulkarni Sakil, Huang Jiansheng, Tycksen Eric, Cliften Paul F, Rudnick David A
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
PPAR Res. 2020 Sep 10;2020:3817573. doi: 10.1155/2020/3817573. eCollection 2020.
Pioglitazone (Pio) is a thiazolidinedione (TZD) insulin-sensitizing drug whose effects result predominantly from its modulation of the transcriptional activity of peroxisome proliferator-activated-receptor-gamma (PPAR). Pio is used to treat human insulin-resistant diabetes and also frequently considered for treatment of nonalcoholic steatohepatitis (NASH). In both settings, Pio's beneficial effects are believed to result primarily from its actions on adipose PPAR activity, which improves insulin sensitivity and reduces the delivery of fatty acids to the liver. Nevertheless, a recent clinical trial showed variable efficacy of Pio in human NASH. Hepatocytes also express PPAR, and such expression increases with insulin resistance and in nonalcoholic fatty liver disease (NAFLD). Furthermore, mice that overexpress hepatocellular PPAR and Pio-treated mice with extrahepatic PPAR gene disruption develop features of NAFLD. Thus, Pio's direct impact on hepatocellular gene expression might also be a determinant of this drug's ultimate influence on insulin resistance and NAFLD. Previous studies have characterized Pio's PPAR-dependent effects on hepatic expression of specific adipogenic, lipogenic, and other metabolic genes. However, such transcriptional regulation has not been comprehensively assessed. The studies reported here address that consideration by genome-wide comparisons of Pio's hepatic transcriptional effects in wildtype (WT) and liver-specific PPAR-knockout (KO) mice given either control or high-fat (HFD) diets. The results identify a large set of hepatic genes for which Pio's liver PPAR-dependent transcriptional effects are concordant with its effects on RXR-DNA binding in WT mice. These data also show that HFD modifies Pio's influence on a subset of such transcriptional regulation. Finally, our findings reveal a broader influence of Pio on PPAR-dependent hepatic expression of nuclear genes encoding mitochondrial proteins than previously recognized. Taken together, these studies provide new insights about the tissue-specific mechanisms by which Pio affects hepatic gene expression and the broad scope of this drug's influence on such regulation.
吡格列酮（Pio）是一种噻唑烷二酮类（TZD）胰岛素增敏药物，其作用主要源于对过氧化物酶体增殖物激活受体γ（PPAR）转录活性的调节。Pio用于治疗人类胰岛素抵抗性糖尿病，也常被考虑用于治疗非酒精性脂肪性肝炎（NASH）。在这两种情况下，Pio的有益作用被认为主要源于其对脂肪组织PPAR活性的作用，这可提高胰岛素敏感性并减少脂肪酸向肝脏的输送。然而，最近一项临床试验显示Pio在人类NASH中的疗效存在差异。肝细胞也表达PPAR，并且这种表达随着胰岛素抵抗和非酒精性脂肪性肝病（NAFLD）而增加。此外，过表达肝细胞PPAR的小鼠和用肝外PPAR基因敲除处理的Pio治疗小鼠会出现NAFLD的特征。因此，Pio对肝细胞基因表达的直接影响也可能是该药物对胰岛素抵抗和NAFLD最终影响的一个决定因素。先前的研究已经描述了Pio对特定脂肪生成、脂质生成和其他代谢基因肝脏表达的PPAR依赖性影响。然而，这种转录调控尚未得到全面评估。本文报道的研究通过在给予对照或高脂（HFD）饮食的野生型（WT）和肝脏特异性PPAR基因敲除（KO）小鼠中对Pio的肝脏转录作用进行全基因组比较来解决这一问题。结果确定了一大组肝脏基因，Pio对这些基因的肝脏PPAR依赖性转录作用与其对WT小鼠中RXR-DNA结合的作用一致。这些数据还表明，HFD改变了Pio对这类转录调控子集的影响。最后，我们的研究结果揭示了Pio对编码线粒体蛋白的核基因的PPAR依赖性肝脏表达的影响比以前认识到的更广泛。综上所述，这些研究为Pio影响肝脏基因表达的组织特异性机制以及该药物对这种调控的广泛影响提供了新的见解。
