Apolipoprotein J is a hepatokine regulating muscle glucose metabolism and insulin sensitivity

Ji A. Seo, Min Cheol Kang, Won Mo Yang, Won Min Hwang, Sang Soo Kim, Soo Hyun Hong, Jee In Heo, Achana Vijyakumar, Leandro Pereira de Moura, Aykut Uner, Hu Huang, Seung Hwan Lee, Inês S. Lima, Kyong Soo Park, Min Seon Kim, Yossi Dagon, Thomas E. Willnow, Vanita Aroda, Theodore P. Ciaraldi, Robert R. HenryYoung Bum Kim

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Abstract

Crosstalk between liver and skeletal muscle is vital for glucose homeostasis. Hepatokines, liver-derived proteins that play an important role in regulating muscle metabolism, are important to this communication. Here we identify apolipoprotein J (ApoJ) as a novel hepatokine targeting muscle glucose metabolism and insulin sensitivity through a low-density lipoprotein receptor-related protein-2 (LRP2)-dependent mechanism, coupled with the insulin receptor (IR) signaling cascade. In muscle, LRP2 is necessary for insulin-dependent IR internalization, an initial trigger for insulin signaling, that is crucial in regulating downstream signaling and glucose uptake. Of physiologic significance, deletion of hepatic ApoJ or muscle LRP2 causes insulin resistance and glucose intolerance. In patients with polycystic ovary syndrome and insulin resistance, pioglitazone-induced improvement of insulin action is associated with an increase in muscle ApoJ and LRP2 expression. Thus, the ApoJ-LRP2 axis is a novel endocrine circuit that is central to the maintenance of normal glucose homeostasis and insulin sensitivity.

Original languageEnglish
Article number2024
JournalNature Communications
Volume11
Issue number1
DOIs
StatePublished - 1 Dec 2020

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Seo, J. A., Kang, M. C., Yang, W. M., Hwang, W. M., Kim, S. S., Hong, S. H., Heo, J. I., Vijyakumar, A., Pereira de Moura, L., Uner, A., Huang, H., Lee, S. H., Lima, I. S., Park, K. S., Kim, M. S., Dagon, Y., Willnow, T. E., Aroda, V., Ciaraldi, T. P., ... Kim, Y. B. (2020). Apolipoprotein J is a hepatokine regulating muscle glucose metabolism and insulin sensitivity. Nature Communications, 11(1), [2024]. https://doi.org/10.1038/s41467-020-15963-w