Insulin-induced CARM1 upregulation facilitates hepatocyte proliferation.
Previously, we reported that CARM1 undergoes ubiquitination-dependent degradation in renal podocytes. It was also reported that CARM1 is necessary for fasting-induced hepatic gluconeogenesis. Based on these reports, we hypothesized that treatment with insulin, a hormone typically present under the 'fed' condition, would inhibit gluconeogenesis via CARM1 degradation. HepG2 cells, AML-12 cells, and rat primary hepatocytes were treated with insulin to confirm CARM1 downregulation. Surprisingly, insulin treatment increased CARM1 expression in all cell types examined. Furthermore, treatment with insulin increased histone 3 methylation at arginine 17 and 26 in HepG2 cells. To elucidate the role of insulin-induced CARM1 upregulation, the HA-CARM1 plasmid was transfected into HepG2 cells. CARM1 overexpression did not increase the expression of lipogenic proteins generally increased by insulin signaling. Moreover, CARM1 knockdown did not influence insulin sensitivity. Insulin is known to facilitate hepatic proliferation. Like insulin, CARM1 overexpression increased CDK2 and CDK4 expression. In addition, CARM1 knockdown reduced the number of insulin-induced G2/M phase cells. Moreover, GFP-CARM1 overexpression increased the number of G2/M phase cells. Based on these results, we concluded that insulin-induced CARM1 upregulation facilitates hepatocyte proliferation. These observations indicate that CARM1 plays an important role in liver pathophysiology.
College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
Chul-Gon
CG
Yeom
College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
Dong-Il
DI
Kim
College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
Min-Jung
MJ
Park
College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
Joo-Hee
JH
Choi
Jeollanamdo Forest Resources Research Institute, Naju 520-833, Republic of Korea.
Jieun
J
Jeong
Jeollanamdo Forest Resources Research Institute, Naju 520-833, Republic of Korea.
Anjin
A
Wi
Jeollanamdo Forest Resources Research Institute, Naju 520-833, Republic of Korea.
Whoashig
W
Park
College of Veterinary Medicine, Seoul National University, Seoul 151-741, Republic of Korea.
Ho-Jae
HJ
Han
College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address: parksh@chonnam.ac.kr.
Soo-Hyun
SH
Park
D002453:Cell Cycle; D049109:Cell Proliferation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000502:physiology*; D050155:Lipogenesis / Q000502:physiology; D008745:Methylation; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*
D006657:Histones; D007328:Insulin; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1
CARM1; Hepatocyte; Histone methylation; Insulin; PRMT4; Proliferation