title: Protein phosphatase 4 (PP4) functions as a critical regulator in tumor necrosis factor (TNF)-α-induced hepatic insulin resistance.
abstract: Protein phosphatase 4 (PP4) was shown to participate in multiple cellular processes, including DNA damage response, cell cycle and embryo development. Recent studies demonstrated a looming role of PP4 in glucose metabolism. However, whether PP4 is involved in hepatic insulin resistance remains poorly understood. The objective of this study was to estimate the role of PP4 in tumor necrosis factor (TNF)-α-induced hepatic insulin resistance. db/db mice and TNF-α-treated C57BL/6J mice were used as hepatic insulin resistance animal models. In vitro models were established in both HepG2 cells and primary hepatocytes by TNF-α treatment. We found that increased expression and activity of PP4 occurred in the livers of db/db mice and TNF-α-induced hepatic insulin resistance both in vitro and in vivo. Actually, PP4 silencing and suppression of PP4 activity ameliorated TNF-α-induced hepatic insulin resistance, whereas over-expression of PP4 caused insulin resistance. We then further investigated the prodiabetic mechanism of PP4 in TNF-α-induced insulin resistance. We found that PP4 formed a complex with IRS-1 to promote phosphorylation of IRS-1 on serine 307 via JNK activation and reduce the expression of IRS-1. Thus, PP4 is an important regulator in inflammatory related insulin resistance.
authors.affiliation: Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.|The Key Laboratory of Geriatrics, Beijing Hospital &Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Hongye
authors.initials: H
authors.lastname: Zhao
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital &Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Huang
authors.affiliation: Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.|The Key Laboratory of Geriatrics, Beijing Hospital &Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Jiao
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital &Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Hangxiang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Beijing Normal University, 100875, P.R. China.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital &Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Qin
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital &Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Meng
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital &Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Shen
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital &Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Lin
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital &Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Chu
authors.affiliation: Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.|The Key Laboratory of Geriatrics, Beijing Hospital &Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D055504:Insulin Receptor Substrate Proteins; D014409:Tumor Necrosis Factor-alpha; D010749:Phosphoprotein Phosphatases; C080406:protein phosphatase 4