title: Hepatic FTO expression is increased in NASH and its silencing attenuates palmitic acid-induced lipotoxicity.
abstract: Non-alcoholic steatohepatitis (NASH) is one of the most common causes of liver failure worldwide. It is characterized by excess fat accumulation, inflammation, and increased lipotoxicity in hepatocytes. Currently, there are limited treatment options for NASH due to lack of understanding of its molecular etiology. In the present study, we demonstrate that the expression of fat mass and obesity associated gene (FTO) is significantly increased in the livers of NASH patients and in a rodent model of NASH. Furthermore, using human hepatic cells, we show that genetic silencing of FTO protects against palmitate-induced oxidative stress, mitochondrial dysfunction, ER stress, and apoptosis in vitro. Taken together, our results show that FTO may have a deleterious role in hepatic cells during lipotoxic conditions, and strongly suggest that up-regulation of FTO may contribute to the increased liver damage in NASH.
authors.affiliation: Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 8 College Road, 169857, Singapore; Deparment of Pharmacy, National University of Singapore, 18 Science Drive 4, 117543, Singapore.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lim
authors.affiliation: Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 8 College Road, 169857, Singapore. Electronic address: jin.Zhou@Duke-Nus.Edu.Sg.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 8 College Road, 169857, Singapore.
authors.forename: Rohit A
authors.initials: RA
authors.lastname: Sinha
authors.affiliation: Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 8 College Road, 169857, Singapore.
authors.forename: Brijesh K
authors.initials: BK
authors.lastname: Singh
authors.affiliation: Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 8 College Road, 169857, Singapore.
authors.forename: Sujoy
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Pathology, Singapore General Hospital, Singapore, Singapore.
authors.forename: Kiat-Hon
authors.initials: KH
authors.lastname: Lim
authors.affiliation: Clinical Science, Duke-NUS Graduate Medical School, Singapore, Singapore; Division of Surgical Oncology, National Cancer Centre Singapore, Singapore.
authors.forename: Pierce Kah-Hoe
authors.initials: PK
authors.lastname: Chow
authors.affiliation: Deparment of Pharmacy, National University of Singapore, 18 Science Drive 4, 117543, Singapore.
authors.forename: Esther C Y
authors.initials: ECY
authors.lastname: Woon
authors.affiliation: Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 8 College Road, 169857, Singapore. Electronic address: paul.yen@duke-nus.edu.sg.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Yen
mesh_terms: D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D002518:Ceramides / Q000737:chemistry; D059865:Endoplasmic Reticulum Stress; D005786:Gene Expression Regulation; D020868:Gene Silencing; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D010101:Oxygen Consumption; D019308:Palmitic Acid / Q000494:pharmacology
chemical_list: D002518:Ceramides; D019308:Palmitic Acid; C524916:FTO protein, mouse; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human
keywords: Fat and obesity associated (FTO) gene; Lipotoxicity; Non-alcoholic steatohepatitis (NASH); Obesity