SIRT1 Disruption in Human Fetal Hepatocytes Leads to Increased Accumulation of Glucose and Lipids.

Takamasa Tobita,Kazuki Takeishi,Alejandro Soto-Gutierrez,Toshimasa Nakao,Fanying Meng,Chu-Xia Deng,Yang Wang,Jorge Guzman-Lepe,Alexandra Collin De L’Hortet,Hervé Guillou

doi:10.1371/journal.pone.0149344

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.

Highlights

SIRT1 (Silent mating type information regulation 2 homolog) belongs to the Sirtuins family of proteins and codes for a class III NAD-dependent histone deacetylase (HDACs)
It has been shown that the deletion of SIRT1 leads to hepatic steatosis with normal and high fat diet [7, 22]
We found that all four major genes involved in de novo—fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), stearoyl-CoA desaturase (SCD), and elongase of long chain fatty acids family 6 (ELOVL6)—were upregulated when the cells were exposed to SIRT1 inhibitor (Fig 3A, 3B, 3C and 3D)

Summary

Introduction

SIRT1 (Silent mating type information regulation 2 homolog) belongs to the Sirtuins family of proteins and codes for a class III NAD-dependent histone deacetylase (HDACs). The functions of SIRT1 have been essentially linked to the regulation of growth, apoptosis, metabolism and aging, responding to environmental cues through NAD+ levels [1,2,3,4]. SIRT1 deacetylates a wide range of targets, leading to epigenetic modifications of histones and modulation of transcription factors or metabolic enzymes [3]. SIRT1 has been thought to be a molecular link between the adaptive transcriptional response and the metabolic status [5, 6]. Recent studies performed on the liver of mice showed the key role of SIRT1 in the development of fatty liver through the regulation of proteins involved in lipid [7, 8] and carbohydrate

Methods

Results

Conclusion