Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states
Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states
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DOI：
10.1016/j.cmet.2007.05.002
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发表时间：
2007-06-01
期刊：
影响因子：
29
通讯作者：
Maratos-Flier, Eleftheria
中科院分区：
文献类型：
--
作者：
Badman, Michael K.;Pissios, Pavlos;Maratos-Flier, Eleftheria
喂食高脂肪、低碳水化合物生酮饮食（KID）的小鼠表现出肝脏代谢和能量稳态的显著变化。在这里，我们确定肝源性成纤维细胞生长因子21（FGF21）作为内分泌调节的酮症状态。FGF21的肝脏表达和循环水平由KD和禁食诱导，通过再喂养迅速抑制，并且在很大程度上位于PPAR α的下游。重要的是，腺病毒敲低KD喂养小鼠的肝FGF21导致脂肪肝、脂血和血清酮减少，这至少部分是由于控制脂质和酮代谢的关键基因表达改变。因此，肝中FGF 21的诱导是KD诱导的肝脂质氧化、甘油三酯清除和生酮的正常激活所必需的。这些发现确定肝FGF21作为脂质稳态的关键调节剂，并确定这种肝激素的生理作用。
Mice fed a high-fat, low-carbohydrate ketogenic diet (KID) exhibit marked changes in hepatic metabolism and energy homeostasis. Here, we identify liver-derived fibroblast growth factor 21 (FGF21) as an endocrine regulator of the ketotic state. Hepatic expression and circulating levels of FGF21 are induced by both KD and fasting, are rapidly suppressed by refeeding, and are in large part downstream of PPAR alpha. Importantly, adenoviral knockdown of hepatic FGF21 in KD-fed mice causes fatty liver, lipemia, and reduced serum ketones, due at least in part to altered expression of key genes governing lipid and ketone metabolism. Hence, induction of FGF21 in liver is required for the normal activation of hepatic lipid oxidation, triglyceride clearance, and ketogenesis induced by KD. These findings identify hepatic FGF21 as a critical regulator of lipid homeostasis and identify a physiological role for this hepatic hormone.