Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
J Lipid Res. 2018 Nov;59(11):2140-2152. doi: 10.1194/jlr.M088419. Epub 2018 Aug 29.
PPARα (PPARA), expressed in most oxidative tissues, is a major regulator of lipid homeostasis; hepatic PPARA plays a critical role during the adaptive fasting response by promoting FA oxidation (FAO). To clarify whether extrahepatic PPARA activity can protect against lipid overload when hepatic PPARA is impaired, lipid accumulation was compared in WT (), total body -null (), and hepatocyte-specific -null () mice that were fasted for 24 h. Histologic staining indicated reduced lipid accumulation in versus mice, and biochemical analyses revealed diminished medium- and long-chain FA accumulation in mouse livers. Hepatic PPARA target genes were suppressed in both mouse models. Serum FFAs increased in all genotypes after fasting but were highest in mice. In mice, FAO genes were increased in brown adipose tissue, heart, and muscle, and total lipase activity was elevated in the muscle and heart, suggesting increased lipid utilization. Thus, extrahepatic PPARA activity reduces systemic lipid load when hepatic lipid metabolism is impaired by elevating FAO and lipase activity in other tissues and, as a result, protects against fasting-induced hepatosteatosis. This has important clinical implications in disease states with impaired hepatic PPARA function, such as nonalcoholic steatohepatitis and nonalcoholic fatty liver disease.
过氧化物酶体增殖物激活受体α（PPARA）在大多数氧化组织中表达，是脂质稳态的主要调节剂；肝 PPARA 在适应饥饿反应中起着关键作用，通过促进脂肪酸氧化（FAO）。为了阐明当肝 PPARA 受损时，肝外 PPARA 活性是否可以防止脂质过载，我们比较了野生型（WT）、全身 - 缺失（）和肝特异性 - 缺失（）小鼠在禁食 24 小时后的脂质积累情况。组织学染色表明与 小鼠相比，脂质积累减少，生化分析显示 小鼠肝脏中中链和长链 FA 积累减少。两种小鼠模型中的肝 PPARA 靶基因均受到抑制。禁食后所有基因型的血清游离脂肪酸（FFAs）均增加，但 小鼠的 FFAs 最高。在 小鼠中，褐色脂肪组织、心脏和肌肉中的 FAO 基因增加，肌肉和心脏中的总脂肪酶活性升高，提示脂质利用率增加。因此，当肝脂质代谢受损时，肝外 PPARA 活性通过提高其他组织中的 FAO 和脂肪酶活性来减轻全身脂质负荷，并防止饥饿引起的肝脂肪变性。在肝 PPARA 功能受损的疾病状态下，如非酒精性脂肪性肝炎和非酒精性脂肪性肝病，这具有重要的临床意义。
