Hepatic-Specific Disruption of SIRT6 in Mice Results in Fatty Liver Formation Due to Enhanced Glycolysis and Triglyceride Synthesis

Abstract

Under various conditions mammals have the ability to maintain serum glucose concentration within a narrow range. SIRT1 plays an important role in regulating gluconeogenesis and fat metabolism; however, the underlying mechanisms remain elusive. Here we show that SIRT1 forms a complex with FOXO3a and NRF1 on the SIRT6 promoter and positively regulates expression of SIRT6, which in turn negatively regulates glycolysis, triglyceride synthesis and fat metabolism by deacetylating histone H3 lysine 9 in the promoter of many genes involved in these processes. Liver specific deletion of SIRT6 in mice causes profound alterations in gene expression, leading increased glycolysis, triglyceride synthesis, reduced β-oxidation, and fatty liver formation. Human fatty liver samples exhibited significantly lower levels of SIRT6 than normal controls. Thus, SIRT6 plays a critical role in fat metabolism, and may serve as a novel therapeutic target for treating fatty liver disease, the most common cause of liver dysfunction in humans.

Activation of the Protein Deacetylase SIRT6 by Long-chain Fatty Acids and Widespread Deacylation by Mammalian Sirtuins

“…SIRT6 was shown to negatively control the mRNA expression of glycolytic and lipogenic genes (16,32). This observation is strikingly similar to the decreased mRNA levels of pyruvate kinase (PK) and fatty acid synthase (FAS) that are reported with PUFA treatment in primary hepatocytes (33).…”

FoxO3 Transcription Factor and Sirt6 Deacetylase Regulate Low Density Lipoprotein (LDL)-cholesterol Homeostasis via Control of the Proprotein Convertase Subtilisin/Kexin Type 9 (Pcsk9) Gene Expression

“…According to our data, we speculate that down-regulation of the Pcsk9 gene expression may be responsible for the low LDL-cholesterol phenotype in the Sirt6 transgenic mice. Additionally, Sirt6 also significantly represses fatty acid and cholesterol biosynthetic genes and activates fatty acid oxidation genes (38,43). Apparently, Sirt6 has a salutary effect on lipid homeostasis.…”

“…Because Sirt6 is decreased in the livers of obese animals and humans (38,48), it implicates a potential consequence for the development of hypercholesterolemia, particularly high LDL-cholesterol. Previously, it was reported that systemic overexpression of Sirt6 in mice can lower LDLcholesterol under conditions of either chow or high fat diet; however, the underlying mechanism is not clear (49).…”

“…Sirt6 has been previously shown to regulate hepatic triglyceride metabolism and cholesterol biosynthesis (38,43). To examine which lipoprotein-associated cholesterol might be modulated by Sirt6, we analyzed cholesterol in HDL and LDL/VLDL fractions of sera from control floxed (LoxpT6) and Sirt6 liver-specific knock-out mice (LKOT6).…”

Epigenetic regulation of aging stem cells

“…Understanding the role of Sirtuins in aging stem cells will likely provide insights into the mechanisms that regulate stem cell homeostasis, particularly in response to stress stimuli. In addition, the ability of Sirtuins to regulate both organismal energy metabolism (Banks et al, 2008;Feige et al, 2008;Kim et al, 2010;Ramadori et al, 2010;Zhong et al, 2010) and chromatin may be particularly important for the response of adult stem cells to environmental stimuli such as dietary restriction that are known to promote longevity and delay signs of aging.…”