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

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.

• Authors: 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, Young-Bum Kim
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 2024 (04 24 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32332780 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 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

Topics

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