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

Funding Information: This work was supported by grants from the National Institutes of Health (R01DK111529 and R01DK106076 to Y.-B.K.) and in part by Merit Review Award (I01CX00635) from the United States Department of Veterans Affairs Clinical Sciences Research and Development Service (R.R.H.), grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2018R1D1A1B07049123 to J.A.S. and 2017R1A6A3A03003298 to W.-M.Y.), a grant from the Korean Diabetes Association (2017S-2 to J.A.S.), and a grant from Korea University (K1813091 to J.A.S.). The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. The Animal Metabolic Physiology Core (P30 DK057521 Barbara Kahn) performed in vivo glucose uptake. M.-C.K. is a recipient of a postdoctoral fellowship award from the American Diabetes Association (1-17-PDF-146), I.S.L. is a recipient of FCT fellowship from Portugal (SFRH/BD/71021/2010), and L.P.M is a recipient of São Paulo Research Foundation from Brazil (FAPESP 2013/ 14149-6). We would like to thank Barbara Kahn, Tony Hollenberg, and Terry Flier for helpful discussions, Odile Peroni for technical assistance on in vivo glucose uptake, Amira Klip for the C2C12-myc-Glut4 cell line, Sungman Cho for glucose uptake assays, Jin Sung Park for VLDL-secretion, Wendy Li for Immunofluorescent analysis, Zoltan Arany for myogenin-Cre transgenic mice, Inkyu Lee for ApoJ adenovirus, and Min Bon Hong for ApoJ recombinant protein. Publisher Copyright: © 2020, The Author(s).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.publishersversionpublishe

Apolipoprotein J is a hepatokine regulating muscle glucose metabolism and insulin sensitivity (Nature Communications, (2020), 11, 1, (2024), 10.1038/s41467-020-15963-w)

Publisher Copyright: © 2020, The Author(s).An amendment to this paper has been published and can be accessed via a link at the top of the paper.publishersversionpublishe