Extrahepatic PPAR modulates fatty acid oxidation and attenuates fasting-induced hepatosteatosis in mice
Extrahepatic PPAR modulates fatty acid oxidation and attenuates fasting-induced hepatosteatosis in mice
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DOI：
10.1194/jlr.m088419
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发表时间：
2018-11-01
影响因子：
6.5
通讯作者：
Gonzalez, Frank J.
中科院分区：
文献类型：
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作者：
Brocker, Chad N.;Patel, Daxesh P.;Gonzalez, Frank J.
PPAR (PPARA) 在大多数氧化组织中表达，是脂质稳态的主要调节因子；肝脏 PPARA 通过促进 FA 氧化 (FAO) 在适应性禁食反应中发挥关键作用。为了阐明当肝脏 PPARA 受损时，肝外 PPARA 活性是否可以防止脂质超载，比较了禁食 24 小时的 WT (Ppara(+/+))、全身 Ppara-null (Ppara(-/-)) 和肝细胞特异性 Ppara-null (Ppara(Hep)) 小鼠的脂质积累。组织学染色表明，与 Ppara(-/-) 小鼠相比，Ppara(Hep) 小鼠的脂质积累减少，生化分析显示 Ppara(Hep) 小鼠肝脏中中链和长链 FA 积累减少。两种小鼠模型中肝脏 PPARA 靶基因均受到抑制。禁食后所有基因型的血清 FFA 均增加，但 Ppara(-/-) 小鼠的血清 FFA 最高。在 Ppara(Hep) 小鼠中，FAO 基因在棕色脂肪组织、心脏和肌肉中增加，并且肌肉和心脏中的总脂肪酶活性升高，表明脂质利用率增加。因此，当其他组织中的FAO和脂肪酶活性升高而导致肝脏脂质代谢受损时，肝外PPARA活性会降低全身脂质负荷，从而防止禁食引起的肝脂肪变性。这对于肝 PPARA 功能受损的疾病状态（例如非酒精性脂肪性肝炎和非酒精性脂肪肝病）具有重要的临床意义。
PPAR (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 (Ppara(+/+)), total body Ppara-null (Ppara(-/-)), and hepatocyte-specific Ppara-null (Ppara(Hep)) mice that were fasted for 24 h. Histologic staining indicated reduced lipid accumulation in Ppara(Hep) versus Ppara(-/-) mice, and biochemical analyses revealed diminished medium- and long-chain FA accumulation in Ppara(Hep) mouse livers. Hepatic PPARA target genes were suppressed in both mouse models. Serum FFAs increased in all genotypes after fasting but were highest in Ppara(-/-) mice. In Ppara(Hep) 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.