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

Nat Commun. 2020 Apr 24;11(1):2024. doi: 10.1038/s41467-020-15963-w.


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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Animals
  • Cell Line
  • Clusterin / blood
  • Clusterin / genetics
  • Clusterin / metabolism*
  • Disease Models, Animal
  • Female
  • Glucose / metabolism*
  • Glucose Clamp Technique
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use
  • Insulin / metabolism
  • Insulin Resistance*
  • Liver / metabolism
  • Low Density Lipoprotein Receptor-Related Protein-2 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-2 / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / metabolism*
  • Pioglitazone / pharmacology
  • Pioglitazone / therapeutic use
  • Polycystic Ovary Syndrome / blood
  • Polycystic Ovary Syndrome / drug therapy
  • Polycystic Ovary Syndrome / metabolism*
  • Receptor, Insulin / metabolism
  • Signal Transduction / drug effects


  • CLU protein, human
  • Clu protein, mouse
  • Clusterin
  • Hypoglycemic Agents
  • Insulin
  • LRP2 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-2
  • Lrp2 protein, mouse
  • Receptor, Insulin
  • Glucose
  • Pioglitazone