AMPK activator-mediated inhibition of endoplasmic reticulum stress ameliorates carrageenan-induced insulin resistance through the suppression of selenoprotein P in HepG2 hepatocytes.
Carrageenan (CGN) has been shown to cause inflammation through toll-like receptor 4, which may play an important role in insulin resistance and type 2 diabetes mellitus. Selenoprotein P (SeP) has recently been identified as a novel hepatokine that causes insulin resistance. Here, we report that treatment of HepG2 cells with CGN increased both CCAAT enhancer binding protein homologous protein (CHOP) and SeP expression. Pretreatment with 4-phenylbutyrate (4-PBA), an endoplasmic reticulum stress inhibitor, and PD98059, a c-Jun N-terminal kinase (JNK) inhibitor, reversed CGN-induced SeP expression. Moreover, both 4-PBA and knock-down of SeP improved CGN-induced insulin resistance. In addition, we found that adenosine monophosphate-activated protein kinase (AMPK) activators ameliorated CGN-induced insulin resistance in addition to suppressing CHOP and SeP expression. In conclusion, CGN-induced ER stress increased the expression of SeP through the JNK pathway, while AMPK activators ameliorated CGN-induced insulin resistance via SeP inhibition through the AMPK-mediated alleviation of ER stress in hepatocytes.
The Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
Tae Woo
TW
Jung
The Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
So Young
SY
Lee
The Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
Ho Cheol
HC
Hong
The Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
Hae Yoon
HY
Choi
The Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
Hye Jin
HJ
Yoo
The Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
Sei Hyun
SH
Baik
The Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea. Electronic address: medica7@gmail.com.
Kyung Mook
KM
Choi
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000293:Adolescent; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D002351:Carrageenan; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008687:Metformin / Q000494:pharmacology; D012265:Ribonucleotides / Q000494:pharmacology; D012459:Salicylates / Q000494:pharmacology; D051149:Selenoprotein P / Q000378:metabolism*
D020536:Enzyme Activators; D012265:Ribonucleotides; D012459:Salicylates; D051149:Selenoprotein P; D000620:Aminoimidazole Carboxamide; D002351:Carrageenan; D008687:Metformin; D048031:JNK Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; C014182:salicylsalicylic acid
AMPK; ER stress; Hepatokine; Insulin resistance; Salsalate; Selenoprotein P