Sun Wei, Nie Tao, Li Kuai, Wu Wenjie, Long Qiaoyun, Feng Tianshi, Mao Liufeng, Gao Yuan, Liu Qing, Gao Xuefei, Ye Dewei, Yan Kaixuan, Gu Ping, Xu Yong, Zhao Xuemei, Chen Kang, Loomes Kerry Martin, Lin Shaoqiang, Wu Donghai, Hui Xiaoyan
Clinical Department of Guangdong Metabolic Disease Research Centre of Integrated Chinese and Western Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong, China.
Key Laboratory of Regenerative Biology, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530 Guangzhou, China; Guangzhou Medical University, Guangzhou, China.
Diabetes. 2021 Oct 21. doi: 10.2337/db21-0363.
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 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.
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.
肝脂肪变性定义为肝内脂质过度蓄积，是NAFLD的第一步。当与其他细胞应激因素共同作用时，这种良性状态会进展为局部和全身的病理状况，如非酒精性脂肪性肝炎（NASH）和胰岛素抵抗。然而，肝脏脂质堆积直接引发的分子事件，就其对肝脏生物学和外周器官的影响而言，仍不清楚。肉碱棕榈酰转移酶1A（CPT1A）是肝脏中长链脂肪酸β-氧化的限速酶。在此，我们利用肝细胞特异性敲除（LKO）小鼠来研究消除肝脏长链脂肪酸代谢的生理后果。
与野生型（WT）同窝小鼠相比，高脂饮食（HFD）喂养的LKO小鼠表现出更严重的肝脂肪变性，但在其他方面可免受饮食诱导的体重增加、胰岛素抵抗、肝脏内质网应激、炎症和损伤。有趣的是，在LKO小鼠中观察到能量消耗增加，同时伴有脂肪组织褐变增强。RNA测序分析显示，过氧化物酶体增殖物激活剂α（PPARα）-成纤维细胞生长因子21（FGF21）轴在LKO小鼠肝脏中被激活。重要的是，抗体介导的FGF21中和消除了LKO小鼠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处理的LKO小鼠的肝脏病理和脂肪褐变。
CPT1A表达缺陷的肝脏呈现出一种健康的脂肪变性状态，可保护免受HFD诱发的肝脏损伤，并以FGF21依赖的方式增强脂肪褐变。抑制肝脏CPT1A可能是治疗肥胖和NAFLD的一种可行策略。
