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The dysfunction of hormone-sensitive lipase induces lipid deposition and reprogramming of nutrient metabolism in fish

Published online by Cambridge University Press:  21 November 2022

Jin-Gang Wang
LANEH, School of Life Sciences, East China Normal University, Shanghai, People’s Republic of China
Si-Han Zhao
LANEH, School of Life Sciences, East China Normal University, Shanghai, People’s Republic of China
Yu-Cheng Qian
LANEH, School of Life Sciences, East China Normal University, Shanghai, People’s Republic of China
Yi-Fan Qian
LANEH, School of Life Sciences, East China Normal University, Shanghai, People’s Republic of China
Yi-Chan Liu
LANEH, School of Life Sciences, East China Normal University, Shanghai, People’s Republic of China
Fang Qiao
LANEH, School of Life Sciences, East China Normal University, Shanghai, People’s Republic of China
Yuan Luo
LANEH, School of Life Sciences, East China Normal University, Shanghai, People’s Republic of China
Mei-Ling Zhang
LANEH, School of Life Sciences, East China Normal University, Shanghai, People’s Republic of China
Zhen-Yu Du*
LANEH, School of Life Sciences, East China Normal University, Shanghai, People’s Republic of China
*Corresponding author: Zhen-Yu Du, email


Hormone-sensitive lipase (HSL) is one of the rate-determining enzymes in the hydrolysis of TAG, playing a crucial role in lipid metabolism. However, the role of HSL-mediated lipolysis in systemic nutrient homoeostasis has not been intensively understood. Therefore, we used CRISPR/Cas9 technique and Hsl inhibitor (HSL-IN-1) to establish hsla-deficient (hsla -/-) and Hsl-inhibited zebrafish models, respectively. As a result, the hsla -/- zebrafish showed retarded growth and reduced oxygen consumption rate, accompanied with higher mRNA expression of the genes related to inflammation and apoptosis in liver and muscle. Furthermore, hsla -/- and HSL-IN-1-treated zebrafish both exhibited severe fat deposition, whereas their expressions of the genes related to lipolysis and fatty acid oxidation were markedly reduced. The TLC results also showed that the dysfunction of Hsl changed the whole-body lipid profile, including increasing the content of TG and decreasing the proportion of phospholipids. In addition, the systemic metabolic pattern was remodelled in hsla -/- and HSL-IN-1-treated zebrafish. The dysfunction of Hsl lowered the glycogen content in liver and muscle and enhanced the utilisation of glucose plus the expressions of glucose transporter and glycolysis genes. Besides, the whole-body protein content had significantly decreased in the hsla -/- and HSL-IN-1-treated zebrafish, accompanied with the lower activation of the mTOR pathway and enhanced protein and amino acid catabolism. Taken together, Hsl plays an essential role in energy homoeostasis, and its dysfunction would cause the disturbance of lipid catabolism but enhanced breakdown of glycogen and protein for energy compensation.

Research Article
© The Author(s), 2022. Published by Cambridge University Press on behalf of The Nutrition Society

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