Cdo1-Camkk2-AMPK axis confers the protective effects of exercise against NAFLD in mice

Min Chen, Jie-Ying Zhu, Wang-Jing Mu, Hong-Yang Luo, Yang Li, Shan Li, Lin-Jing Yan, Ruo-Ying Li and Liang Guo ()
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Min Chen: Shanghai University of Sport
Jie-Ying Zhu: Shanghai University of Sport
Wang-Jing Mu: Shanghai University of Sport
Hong-Yang Luo: Shanghai University of Sport
Yang Li: Shanghai University of Sport
Shan Li: Shanghai University of Sport
Lin-Jing Yan: Shanghai University of Sport
Ruo-Ying Li: Shanghai University of Sport
Liang Guo: Shanghai University of Sport

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Exercise is an effective non-pharmacological strategy for ameliorating nonalcoholic fatty liver disease (NAFLD), but the underlying mechanism needs further investigation. Cysteine dioxygenase type 1 (Cdo1) is a key enzyme for cysteine catabolism that is enriched in liver, whose role in NAFLD remains poorly understood. Here, we show that exercise induces the expression of hepatic Cdo1 via the cAMP/PKA/CREB signaling pathway. Hepatocyte-specific knockout of Cdo1 (Cdo1LKO) decreases basal metabolic rate of the mice and impairs the effect of exercise against NAFLD, whereas hepatocyte-specific overexpression of Cdo1 (Cdo1LTG) increases basal metabolic rate of the mice and synergizes with exercise to ameliorate NAFLD. Mechanistically, Cdo1 tethers Camkk2 to AMPK by interacting with both of them, thereby activating AMPK signaling. This promotes fatty acid oxidation and mitochondrial biogenesis in hepatocytes to attenuate hepatosteatosis. Therefore, by promoting hepatic Camkk2-AMPK signaling pathway, Cdo1 acts as an important downstream effector of exercise to combat against NAFLD.

Date: 2023
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DOI: 10.1038/s41467-023-44242-7

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