title: Major urinary protein 1 interacts with cannabinoid receptor type 1 in fatty acid-induced hepatic insulin resistance in a mouse hepatocyte model.
abstract: Hepatic insulin resistance (HIR) is a metabolic abnormality characterized by increased gluconeogenesis which usually contributes from an elevation of free fatty acids. Cannabinoid receptor type 1 (CB1R) and major urinary protein 1 (MUP1) are thought to play pivotal roles in mitochondrial dysfunction, liver steatosis and insulin resistance. The aim of this study was to explore the role of MUP1 in CB1R-mediated HIR through the dysregulation of mitochondrial function in AML12 mouse hepatocytes challenged with high concentration of free fatty acids (HFFA). Firstly we observed that treatment of AM251, a selective CB1R antagonist, obviously reversed the HFFA-induced reduction of MUP1 protein expression both in vivo and in vitro. Additionally, our results revealed that AM251 also reverted HFFA-mediated decrease of the mRNA level of mitochondrial biogenesis-related factors, mtDNA amount, ATP production, mitochondrial respiratory complexes-I and -III, and mitochondrial membrane potential, thus consequently might correlate with a parallel reduction of ROS production. Meanwhile, AM251 attenuated HFFA-induced impairment of insulin signaling phosphorylation and elevation of phosphoenolpyrvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), two key enzymes of gluconeogenesis. Silence of MUP1 gene abolished the inhibitory effect of AM251 on HFFA-mediated elevation of PEPCK and G6Pase expression, whereas the suppression of insulin signaling and mRNA level of mitochondrial biogenesis-related factors were only partially recovered. Altogether, these findings suggest that the anti-HIR effect of AM251 via improvement of mitochondrial functions might occur in a MUP1-dependent manner.
authors.affiliation: Institute of Physiology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chin-Chang
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Graduate Institute of Traditional Chinese Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Tzung-Yan
authors.initials: TY
authors.lastname: Lee
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ching-Fai
authors.initials: CF
authors.lastname: Kwok
authors.affiliation: Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yung-Pei
authors.initials: YP
authors.lastname: Hsu
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Kuang-Chung
authors.initials: KC
authors.lastname: Shih
authors.affiliation: Institute of Physiology, National Yang-Ming University, Taipei, Taiwan; Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yan-Jie
authors.initials: YJ
authors.lastname: Lin
authors.affiliation: Institute of Physiology, National Yang-Ming University, Taipei, Taiwan; Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan. Electronic address: ltho@vghtpe.gov.tw.
authors.forename: Low-Tone
authors.initials: LT
authors.lastname: Ho
mesh_terms: D000818:Animals; D015153:Blotting, Western; D059305:Diet, High-Fat; D005227:Fatty Acids / Q000378:metabolism*; D020868:Gene Silencing; D022781:Hepatocytes / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010880:Piperidines / Q000494:pharmacology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D010880:Piperidines; D011506:Proteins; D011720:Pyrazoles; D017382:Reactive Oxygen Species; D043884:Receptor, Cannabinoid, CB1; C035737:major urinary proteins; C103505:AM 251
keywords: Cannabinoid receptor type 1; Hepatic insulin resistance; Major urinary protein 1; Mitochondrial dysfunction