American Diabetes Association
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Hepatic CPT1A Facilitates Liver-Adipose Cross-Talk via Induction of FGF21 in Mice

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posted on 2021-10-21, 18:08 authored by Wei Sun, Tao Nie, Kuai Li, Wenjie Wu, Qiaoyun Long, Tianshi Feng, Liufeng Mao, Yuan Gao, Qing Liu, Xuefei Gao, Dewei Ye, Kaixuan Yan, Ping Gu, Yong Xu, Xuemei Zhao, Kang Chen, Kerry Martin Loomes, Shaoqiang Lin, Donghai Wu, Xiaoyan Hui
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 other 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.


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.


This study was supported by Frontier Research Program of Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory, 2018GZR110105019), Guangzhou International Collaborative Grant (2019A050510027), International Partnership Program of the Chinese Academy of Sciences (154144KYSB20180063), National Natural Science Foundation of China (NSFC) - Excellent Young Scientists Fund (Hong Kong and Macau) (81922079), National Natural Science Foundation of China (81970729, 81670800, 81774134), Science and Technology Planning Project of Guangdong Province, China (2020B1212060052), Guangdong Provincial Public Interest Research and Capacity Building Projects (2014A010107024) and Natural Science Foundation of Jiangsu Province of China (BK20171331).


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