European Genomic Institute for Diabetes, Lille, France; INSERM UMR1011, F-59000, Lille, France; University Lille 2, Lille, France; Institut Pasteur de Lille, Lille, France.
Hepatology. 2014 Nov;60(5):1593-606. doi: 10.1002/hep.27297. Epub 2014 Oct 1.
Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and strongly associated with central obesity, dyslipidemia, and insulin resistance. According to the multiple-hit model of NAFLD pathogenesis, lipid accumulation drives nonalcoholic steatohepatitis (NASH) initiation by triggering oxidative stress, lipotoxicity, and subsequent activation of hepatic inflammatory responses that may progress, in predisposed individuals, to fibrosis and cirrhosis. While there is an unmet therapeutical need for NASH and fibrosis, recent preclinical studies showed that peroxisome proliferator-activated receptor (PPAR)-α agonism can efficiently oppose these symptoms. To dissect the relative contribution of antisteatotic versus anti-inflammatory PPAR-α activities in counteracting dietary-induced liver fibrosis, we used a PPAR-α mutant lacking its DNA-binding-dependent activity on fatty acid metabolism. Liver-specific expression of wild-type or a DNA-binding-deficient PPAR-α in acute and chronic models of inflammation were used to study PPAR-α's anti-inflammatory versus metabolic activities in NASH and fibrosis. Pharmacologically activated PPAR-α inhibited hepatic inflammatory responses and the transition from steatosis toward NASH and fibrosis through a direct, anti-inflammatory mechanism independent of its lipid handling properties.
The transrepression activity of PPAR-α on chronic liver inflammation is sufficient to prevent progression of NASH to liver fibrosis. Dissociated PPAR-α agonists, selectively modulating PPAR-α transrepression activity, could thus be an option to prevent NASH and fibrosis progression.
非酒精性脂肪性肝病（NAFLD）的发病率日益增高，与中心性肥胖、血脂异常和胰岛素抵抗密切相关。根据 NAFLD 发病机制的多打击模型，脂质堆积通过触发氧化应激、脂毒性和随后的肝炎症反应激活，从而启动非酒精性脂肪性肝炎（NASH），在易感个体中，可能进展为纤维化和肝硬化。虽然 NASH 和纤维化存在未满足的治疗需求，但最近的临床前研究表明，过氧化物酶体增殖物激活受体（PPAR）-α 激动剂可以有效地对抗这些症状。为了剖析抗脂肪变性与抗炎 PPAR-α 活性在对抗饮食诱导的肝纤维化中的相对贡献，我们使用了一种缺乏脂肪酸代谢的 DNA 结合依赖性活性的 PPAR-α 突变体。在急性和慢性炎症模型中，肝脏特异性表达野生型或 DNA 结合缺陷型 PPAR-α，用于研究 PPAR-α 在 NASH 和纤维化中的抗炎与代谢活性。药理学激活的 PPAR-α 通过一种直接的抗炎机制，独立于其脂质处理特性，抑制肝炎症反应，并阻止脂肪变性向 NASH 和纤维化的转变。
PPAR-α 的慢性肝炎症反式转录抑制活性足以防止 NASH 进展为肝纤维化。因此，选择性调节 PPAR-α 反式转录抑制活性的分离型 PPAR-α 激动剂可能是预防 NASH 和纤维化进展的一种选择。
