TY - JOUR
T1 - SIRT1 disruption in human fetal hepatocytes leads to increased accumulation of glucose and lipids
AU - Tobita, Takamasa
AU - Guzman-Lepe, Jorge
AU - Takeishi, Kazuki
AU - Nakao, Toshimasa
AU - Wang, Yang
AU - Meng, Fanying
AU - Deng, Chu Xia
AU - De L'Hortet, Alexandra Collin
AU - Soto-Gutierrez, Alejandro
N1 - Funding Information:
Funding from the US National Institutes of Health (DK099257 to A.S.-G., UH3TR000503 and ES022606 subcontract to A.S.-G.), and the Competitive Medical Research Fund Program from UPMC Health System to A.S.-G. Laboratory of Developmental Biology was supported by NIH Award Number 5R24HD000836 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development.
Publisher Copyright:
© 2016 Tobita et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2016/2
Y1 - 2016/2
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0149344
DO - 10.1371/journal.pone.0149344
M3 - Article
C2 - 26890260
AN - SCOPUS:84960533313
SN - 1932-6203
VL - 11
JO - PloS one
JF - PloS one
IS - 2
M1 - e0149344
ER -
