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. Henry and Young-Bum Kim ()
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Ji A Seo: Beth Israel Deaconess Medical Center and Harvard Medical School
Min-Cheol Kang: Beth Israel Deaconess Medical Center and Harvard Medical School
Won-Mo Yang: Beth Israel Deaconess Medical Center and Harvard Medical School
Won Min Hwang: Beth Israel Deaconess Medical Center and Harvard Medical School
Sang Soo Kim: Beth Israel Deaconess Medical Center and Harvard Medical School
Soo Hyun Hong: Beth Israel Deaconess Medical Center and Harvard Medical School
Jee-In Heo: Korea University College of Medicine
Achana Vijyakumar: Beth Israel Deaconess Medical Center and Harvard Medical School
Leandro Pereira de Moura: Beth Israel Deaconess Medical Center and Harvard Medical School
Aykut Uner: Beth Israel Deaconess Medical Center and Harvard Medical School
Hu Huang: Beth Israel Deaconess Medical Center and Harvard Medical School
Seung Hwan Lee: Beth Israel Deaconess Medical Center and Harvard Medical School
Inês S. Lima: Beth Israel Deaconess Medical Center and Harvard Medical School
Kyong Soo Park: Seoul National University
Min Seon Kim: University of Ulsan, College of Medicine
Yossi Dagon: Beth Israel Deaconess Medical Center and Harvard Medical School
Thomas E. Willnow: Max-Delbrueck-Center for Molecular Medicine
Vanita Aroda: Veterans Affairs San Diego Healthcare System (9111 G)
Theodore P. Ciaraldi: Veterans Affairs San Diego Healthcare System (9111 G)
Robert R. Henry: Veterans Affairs San Diego Healthcare System (9111 G)
Young-Bum Kim: Beth Israel Deaconess Medical Center and Harvard Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15963-w

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