Secretion of atherogenic risk factor apolipoprotein B-100 is increased by a potential mechanism of JNK/PKC-mediated insulin resistance in liver cells.

Apolipoprotein B-100 (ApoB) is the main protein of the atherogenic lipoproteins and plasma ApoB levels reflect the total numbers of atherogenic lipoproteins. Induction of insulin resistance was accompanied by a considerable rise in the production of hepatic very low density lipoprotein (VLDL) containing ApoB and triglyceride. Increased plasma levels of ApoB and triglyceride in VLDL are common characteristics of the dyslipidemia associated with insulin resistance and type 2 diabetes mellitus. Thus, we investigate whether phorbol 12-myristate-13-acetate (PMA)-induced insulin resistance affects the increase of ApoB secretion. PMA increased ApoB secretion and transcriptional level of microsomal triglyceride transfer protein (MTP). PMA treatment also resulted in increase of insulin receptor substrate 1 (IRS1) serine312 (Ser312) and serine1101 (Ser1101) phosphorylation and induction of IRS1 degradation. Additionally, PMA induced activation of c-jun N-terminal kinase (JNK) and protein kinase C (PKC) isoforms (alpha, betaI, delta, zeta, theta), and reduced AKT8 virus oncogene cellular homolog (AKT) activation in a time dependent manner. PMA-induced ApoB secretion, MTP promoter activities, and IRS1 degradation was significantly decreased by treatment of JNK and PKCs inhibitors. Orthovanadate, a potent tyrosine phosphatase inhibitor, increased tyrosine phosphorylation of IRS1 and decreased ApoB secretion of Chang liver cells although PMA was co-treated. From the results, it was concluded that PMA-induced insulin resistance, through induction of serine phosphorylation of IRS1 mediated by activated JNK and PKCs, increases ApoB secretion in Chang liver cells.

Jin UH ，Kang YJ ，Chang YC ，Kim CH ... -  《-》

Tumor necrosis factor-alpha directly stimulates the overproduction of hepatic apolipoprotein B100-containing VLDL via impairment of hepatic insulin signaling.

Qin B ，Anderson RA ，Adeli K 《AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY》

Phorbol 12-myristate 13-acetate protects against tumor necrosis factor (TNF)-induced necrotic cell death by modulating the recruitment of TNF receptor 1-associated death domain and receptor-interacting protein into the TNF receptor 1 signaling complex: Im

Byun HS ，Park KA ，Won M ，Yang KJ ，Shin S ，Piao L ，Kwak JY ，Lee ZW ，Park J ，Seok JH ，Liu ZG ，Hur GM ... -  《MOLECULAR PHARMACOLOGY》

Salicylic acid reverses phorbol 12-myristate-13-acetate (PMA)- and tumor necrosis factor alpha (TNFalpha)-induced insulin receptor substrate 1 (IRS1) serine 307 phosphorylation and insulin resistance in human embryonic kidney 293 (HEK293) cells.

Jiang G ，Dallas-Yang Q ，Liu F ，Moller DE ，Zhang BB ... -  《JOURNAL OF BIOLOGICAL CHEMISTRY》

Translational control of apolipoprotein B mRNA via insulin and the protein kinase C signaling cascades: evidence for modulation of RNA-protein interactions at the 5'UTR.

Sidiropoulos KG ，Zastepa A ，Adeli K 《ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS》