title: Microsomal triglyceride transfer protein inhibition induces endoplasmic reticulum stress and increases gene transcription via Ire1α/cJun to enhance plasma ALT/AST.
abstract: Microsomal triglyceride transfer protein (MTP) is a target to reduce plasma lipids because of its indispensable role in triglyceride-rich lipoprotein biosynthesis. MTP inhibition in Western diet fed mice decreased plasma triglycerides/cholesterol, whereas increasing plasma alanine/aspartate aminotransferases (ALT/AST) and hepatic triglycerides/free cholesterol. Free cholesterol accumulated in the endoplasmic reticulum (ER) and mitochondria resulting in ER and oxidative stresses. Mechanistic studies revealed that MTP inhibition increased transcription of the GPT/GOT1 genes through up-regulation of the IRE1α/cJun pathway leading to increased synthesis and release of ALT1/AST1. Thus, transcriptional up-regulation of GPT/GOT1 genes is a major mechanism, in response to ER stress, elevating plasma transaminases. Increases in plasma and tissue transaminases might represent a normal response to stress for survival.
authors.affiliation: School of Graduate Studies, Molecular and Cell Biology Program, State University of New York Downstate Medical Center, Brooklyn, New York 11203; Departments of Cell Biology and Pediatrics, State University of New York Downstate Medical Center, Brooklyn, New York 11203.
authors.forename: Joby
authors.initials: J
authors.lastname: Josekutty
authors.affiliation: Departments of Cell Biology and Pediatrics, State University of New York Downstate Medical Center, Brooklyn, New York 11203.
authors.forename: Jahangir
authors.initials: J
authors.lastname: Iqbal
authors.affiliation: Advanced Scientific Research Leaders Development Unit, Gunma University, Gunma, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Iwawaki
authors.affiliation: Nara Institute of Science and Technology, Nara, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kohno
authors.affiliation: Departments of Cell Biology and Pediatrics, State University of New York Downstate Medical Center, Brooklyn, New York 11203. Electronic address: Mahmood.Hussain@downstate.edu.
authors.forename: M Mahmood
authors.initials: MM
authors.lastname: Hussain
mesh_terms: D000410:Alanine Transaminase / Q000097:blood*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D045744:Cell Line, Tumor; D002469:Cell Separation; D002470:Cell Survival; D002784:Cholesterol / Q000378:metabolism; D004032:Diet; D059865:Endoplasmic Reticulum Stress; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D016755:Proto-Oncogene Proteins c-jun; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; D002784:Cholesterol; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: Cardiovascular Disease; Cell Metabolism; Cholesterol; Endoplasmic Reticulum Stress; Lipid Binding Protein; Lipid Metabolism; Lipids; Lipoprotein; Lipoprotein Metabolism; Liver Injury