The reduction of SIRT1 in livers of old mice leads to impaired body homeostasis and to inhibition of liver proliferation

Abstract

Age declines liver functions, leading to the development of age-associated diseases. A member of the sirtuins family, SIRT1, is involved in the control of glucose homeostasis and fat metabolism. Because aging livers have alterations in glucose and fat metabolism, we examined a possible role of SIRT1 in these alterations. We found that aged livers have a reduced expression of SIRT1 and have lost proper control of the regulation of SIRT1 after partial hepatectomy (PH). Down-regulation of SIRT1 in the liver of old mice is mediated by CCAAT/Enhancer Binding Protein/histone deacetylase 1 (C/EBPβ-HDAC1) complexes, which bind to and repress the SIRT1 promoter. In the livers of young mice, SIRT1 is activated after PH and supports high levels of glucose and triglycerides during liver regeneration. In old mice, however, C/EBPβ-HDAC1–mediated repression of the SIRT1 promoter blocks activation of SIRT1, leading to low levels of glucose and triglycerides during liver regeneration. Down-regulation of SIRT1 in the livers of young mice resulted in alterations similar to those observed in the livers of old mice, whereas the normalization of SIRT1 in the livers of old mice corrects the levels of glucose and triglycerides after PH. The normalization of SIRT1 in old mice also improves liver regeneration via the elimination of the C/EBPα-Brm complex. These studies showed a critical role of the reduction of SIRT1 in age-associated liver dysfunctions and provide a potential tool for the correction of liver functions in old patients after surgical resections.

Effects of aging on liver microcirculatory function and sinusoidal phenotype

“…In addition, we observed an increase in hepatic oxidative stress, with multiple harmful consequences, that may derive from an imbalance between pro‐ and anti‐oxidants, together with increased hepatic lipid content, a well‐known source of cellular oxidative stress. In an important way, oxidative stress could also contribute to potentiate the senescence pathways, and vice versa, thus creating a deleterious vicious cycle in the aged liver (Jin, Iakova, Jiang, Medrano, & Timchenko, 2011; Sharpless & De Pinho, 2004). …”

Age-associated Change of C/EBP Family Proteins Causes Severe Liver Injury and Acceleration of Liver Proliferation after CCl4 Treatments

“…One of the critical and early steps of the cascade of alterations in young S193D and old WT mice is the elevation of a dominant negative isoform of C/EBP␤, C/EBP␤-LIP. In addition to elevation of C/EBP␤-LIP, livers of S193D mice contain high levels of C/EBP␣-HDAC1 complexes that also repress C/EBP-dependent promoters (6,18). As the result, livers of old WT and young S193D mice contain high levels of two repressors of the gene expression, C/EBP␣-HDAC1 complexes and C/EBP␤-LIP.…”

“…We found that C/EBP␣ and C/EBP␤ also interact with these sites in liver nuclear extracts (data not shown). Our previous reports and studies of C/EBP␣ and FXR promoters in this work showed that, in S193D mice, C/EBP␣ forms complexes with histone deacetylase 1 (HDAC1) and these complexes repress target promoters (17,18). Given high affinity sites for C/EBP␣ and C/EBP␤-LIP within the TERT promoter, we examined the hypothesis that C/EBP␣-HDAC1 complexes and C/EBP␤-LIP repress the TERT promoter in livers of S193D mice.…”

“…The sequences of PCR primers were as follows: mC/EBP␣: 5Ј-ATG-GAGTCGGCCGACTTCTAC-3Ј (forward) and 5Ј-CGTCTCGT-GCTCGCAGATGCC-3Ј (reverse); mCUGBP1: 5Ј-TCTGGGA-AAACCTGTGGATA-3Ј (forward) and 5Ј-CACAAAAAGCA-GCTGGAAAT-3Ј(reverse); ␤-actin: 5Ј-TCTTGGGTATGGAA-TCCTGTGGCA-3Ј (forward) and 5Ј-ACTCCTGCTTGCTGA-TCCACATCT-3Ј (reverse); primers for mFXR and mTERT were the same as in references (18,23).…”

“…Another member of C/EBP family, C/EBP␤, is similar to C/EBP␣ and is involved in the regulation of chromatin structure of hepatocytes through interactions with HDAC1 (16,17). It has been shown that the C/EBP␤-HDAC1 complexes are abundant in livers of old mice and repress SIRT1 (18). The formation of C/EBP␤-HDAC1 complexes is mainly controlled by the RNA-binding protein CUGBP1 (14).…”