Hepatic CPT1A Facilitates Liver Adipose Cross Talk via Induction of FGF21 in Mice
Hepatic CPT1A Facilitates Liver Adipose Cross Talk via Induction of FGF21 in Mice
复制标题
肝脏 CPT1A 通过诱导小鼠中的 FGF21 促进肝脏与脂肪的相互作用。
DOI：
10.2337/db21-0363
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发表时间：
2022-01-01
期刊：
影响因子：
7.7
通讯作者：
Hui, Xiaoyan
中科院分区：
文献类型：
--
作者：
Sun, Wei;Nie, Tao;Hui, Xiaoyan
肝脏内肝脏病被定义为过度肝内脂质积累，代表了非酒精性脂肪肝病（NAFLD）的第一步。当与其他细胞应激结合使用时，这种良性状态会发展为局部和系统的病理状况，例如非酒精性脂肪性肝炎和胰岛素抵抗。但是，肝脂质堆积直接引起的分子事件，就其对肝生物学和外围器官的影响而言，尚不清楚。肉碱棕榈酰转移酶1A（CPT1A）是肝脏长链脂肪酸β-氧化的速率限制酶。在这项研究中，我们使用肝细胞特异性CPTLA敲除（LKO）小鼠研究废除肝链脂肪酸代谢的生理后果。与野生型同窝仔相比，高脂饮食（HFD）喂养的LKO小鼠表现出更严重的肝造影症，但否则可以保护饮食诱导的体重增加，胰岛素抵抗，肝内肿瘤性网状胁迫，炎症，炎症和损害。有趣的是，在LKO小鼠中观察到能量消耗增加，并伴有增强的脂肪组织褐变。 RNA测序分析表明，在LKO小鼠的肝脏中激活了过氧化物酶体增殖物激活的受体α-纤维细胞生长因子21（FGF21）轴。重要的是，FGF21的抗体介导的中和消除了LKO小鼠中更健康的代谢表型和脂肪褐变，表明FGF21的升高有助于改善HFD治疗的LKO LKO小鼠的肝脏病理和脂肪褐色。 CPT1A表达不足的肝脏采用健康的脂肪变性状态，可预防HFD诱发的肝损害，并以FGF21依赖性方式增强脂肪褐变。抑制肝CPT1A可以作为治疗肥胖和NAFLD治疗的可行策略。
BACKGROUND & AIMS
Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step of NAFLD. When combined with additional cellular stress, this benign status progresses to local and systemic pathological conditions such as NASH and insulin resistance. However, the molecular events directly caused by hepatic lipid build-up, in terms of its impact on liver biology and peripheral organs, remain unclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme for long chain fatty acid beta-oxidation in the liver. Here we utilise hepatocyte-specific Cpt1a knockout (LKO) mice to investigate the physiological consequences of abolishing hepatic long chain fatty acid metabolism.
APPROACH & RESULTS
Compared to the wild-type (WT) littermates, high fat diet (HFD)-fed LKO mice displayed more severe hepatosteatosis but were otherwise protected against diet-induced weight gain, insulin resistance, hepatic ER stress, inflammation and damage. Interestingly, increased energy expenditure was observed in LKO mice, accompanied by enhanced adipose tissue browning. RNAseq analysis revealed that the peroxisome proliferator activator alpha (PPARα)- fibroblast growth factor 21 (FGF21) axis was activated in liver of LKO mice. Importantly, antibody-mediated neutralization of FGF21 abolished the healthier metabolic phenotype and adipose browning in LKO mice, indicating that the elevation of FGF21 contributes to the improved liver pathology and adipose browning in HFD-treated LKO mice.
CONCLUSIONS
Liver with deficient CPT1A expression adopts a healthy steatotic status that protects against HFD-evoked liver damage and potentiates adipose browning in an FGF21-dependent manner. Inhibition of hepatic CPT1A may serve as a viable strategy for the treatment of obesity and NAFLD.