title: SIRT1 Disruption in Human Fetal Hepatocytes Leads to Increased Accumulation of Glucose and Lipids.
abstract: There are unprecedented epidemics of obesity, such as type II diabetes and non-alcoholic fatty liver diseases (NAFLD) in developed countries. A concerning percentage of American children are being affected by obesity and NAFLD. Studies have suggested that the maternal environment in utero might play a role in the development of these diseases later in life. In this study, we documented that inhibiting SIRT1 signaling in human fetal hepatocytes rapidly led to an increase in intracellular glucose and lipids levels. More importantly, both de novo lipogenesis and gluconeogenesis related genes were upregulated upon SIRT1 inhibition. The AKT/FOXO1 pathway, a major negative regulator of gluconeogenesis, was decreased in the human fetal hepatocytes inhibited for SIRT1, consistent with the higher level of gluconeogenesis. These results indicate that SIRT1 is an important regulator of lipid and carbohydrate metabolisms within human fetal hepatocytes, acting as an adaptive transcriptional response to environmental changes.
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Tobita
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Jorge
authors.initials: J
authors.lastname: Guzman-Lepe
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Takeishi
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Nakao
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.|Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Fanying
authors.initials: F
authors.lastname: Meng
authors.affiliation: Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, China.
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Collin de l'Hortet
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.|Thomas E Starzl Transplant Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.|McGowan Institute for Regenerative Medicine; Pittsburgh, Pennsylvania, United States of America.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Soto-Gutierrez
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D053898:Biosynthetic Pathways / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D050155:Lipogenesis / Q000187:drug effects; D008297:Male; D009284:Naphthols / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D001549:Benzamides; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D009284:Naphthols; C439060:sirtinol; D051057:Proto-Oncogene Proteins c-akt; D056564:Sirtuin 1; D005947:Glucose