Limits...
SIRT1-metabolite binding histone macroH2A1.1 protects hepatocytes against lipid accumulation.

Pazienza V, Borghesan M, Mazza T, Sheedfar F, Panebianco C, Williams R, Mazzoccoli G, Andriulli A, Nakanishi T, Vinciguerra M - Aging (Albany NY) (2014)

Bottom Line: The functional significance of this binding is unknown.Here we show that over-expression of macroH2A1.1, but not of macroH2A1.2, is able to protect hepatocytes against lipid accumulation.MacroH2A1.1 over-expressing cells display ameliorated glucose metabolism, reduced expression of lipidogenic genes and fatty acids content.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Sciences, Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.

ABSTRACT
Non-alcoholic-fatty-liver-disease (NAFLD) encompasses conditions associated to fat deposition in the liver, which are generally deteriorated during the aging process. MacroH2A1, a variant of histone H2A, is a key transcriptional regulator involved in tumorigenic processes and cell senescence, and featuring two alternatively splicing isoforms, macroH2A1.1 and macroH2A1.2. MacroH2A1.1 binds with high affinity O-acetyl ADP ribose, a small metabolite produced by the reaction catalysed by NAD+-dependent deacetylase SIRT1, whereas macroH2A1.2 is unable to do so. The functional significance of this binding is unknown. We previously reported that the hepatic levels of macroH2A1.1 and macroH2A1.2 are differentially expressed in mice models of NAFLD. Here we show that over-expression of macroH2A1.1, but not of macroH2A1.2, is able to protect hepatocytes against lipid accumulation. MacroH2A1.1 over-expressing cells display ameliorated glucose metabolism, reduced expression of lipidogenic genes and fatty acids content. SIRT1/macroH2A1.1-dependent epigenetic regulation of lipid metabolism may be relevant to NAFLD development.

Show MeSH

Related in: MedlinePlus

Differential effects of macroH2A1.1 and macroH2A1.2 on the expression of genes involved in lipid and carbohydrate metabolism in Hepa1-6 cells. 84 genes contained in a commercially available fatty liver array were measured by qRT-PCR in Hepa1-6 cells transiently transfected and treated with FFA, as described in the legends of Figures 1 and 2. Results were clustered in four functional processes (carbohydrate metabolism, A; beta-oxidation, B; lipid metabolism, C; cholesterol transport, D), built on a number of complementary system analyses of biological pathways (see Supplemental Materials and Methods). Results of gene expression in each histogram are represented as % of the FFA-treated mock-transfected (blue), FFA-treated macroH2A1.1-overexpressing (green) or FFA-treated macroH2A1.2 – overexpressing (red) condition related to their respective untreated controls. Results are expressed as percentage of controls, means ± SEM of two independent experiments. *p<0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3927808&req=5

Figure 5: Differential effects of macroH2A1.1 and macroH2A1.2 on the expression of genes involved in lipid and carbohydrate metabolism in Hepa1-6 cells. 84 genes contained in a commercially available fatty liver array were measured by qRT-PCR in Hepa1-6 cells transiently transfected and treated with FFA, as described in the legends of Figures 1 and 2. Results were clustered in four functional processes (carbohydrate metabolism, A; beta-oxidation, B; lipid metabolism, C; cholesterol transport, D), built on a number of complementary system analyses of biological pathways (see Supplemental Materials and Methods). Results of gene expression in each histogram are represented as % of the FFA-treated mock-transfected (blue), FFA-treated macroH2A1.1-overexpressing (green) or FFA-treated macroH2A1.2 – overexpressing (red) condition related to their respective untreated controls. Results are expressed as percentage of controls, means ± SEM of two independent experiments. *p<0.05.

Mentions: Moreover, data were clustered in undirected graphs, representing the above mentioned four processes of carbohydrate metabolism, beta-oxidation, lipid metabolism/transport, and cholesterol metabolism transport, where the thickness of the edges between genes correspond to the different degree of reliability of interaction, based on a number of heterogeneous data sources (protein domains, co-expression, co-localization, genetic interactions, pathways, physical and predicted interactions) (Figure 5A-D, S2A-D). In Hepa1-6, macroH2A1.1 over-expression induced, upon FFA treatment, dramatic changes in the expression of genes involved in carbohydrate metabolism when compared to macroH2A1.2 (downregulation of G6PC, GCK, MLXIPL, PDK4 and RBP4 and upregulation of PCK2 and GSK3B) or to FFA condition (upregulation of G6PC, GCK, MLXIPL and GSK3B and down-regulation of PCK2, PKLR and RBP4) (Figure 5A).


SIRT1-metabolite binding histone macroH2A1.1 protects hepatocytes against lipid accumulation.

Pazienza V, Borghesan M, Mazza T, Sheedfar F, Panebianco C, Williams R, Mazzoccoli G, Andriulli A, Nakanishi T, Vinciguerra M - Aging (Albany NY) (2014)

Differential effects of macroH2A1.1 and macroH2A1.2 on the expression of genes involved in lipid and carbohydrate metabolism in Hepa1-6 cells. 84 genes contained in a commercially available fatty liver array were measured by qRT-PCR in Hepa1-6 cells transiently transfected and treated with FFA, as described in the legends of Figures 1 and 2. Results were clustered in four functional processes (carbohydrate metabolism, A; beta-oxidation, B; lipid metabolism, C; cholesterol transport, D), built on a number of complementary system analyses of biological pathways (see Supplemental Materials and Methods). Results of gene expression in each histogram are represented as % of the FFA-treated mock-transfected (blue), FFA-treated macroH2A1.1-overexpressing (green) or FFA-treated macroH2A1.2 – overexpressing (red) condition related to their respective untreated controls. Results are expressed as percentage of controls, means ± SEM of two independent experiments. *p<0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927808&req=5

Figure 5: Differential effects of macroH2A1.1 and macroH2A1.2 on the expression of genes involved in lipid and carbohydrate metabolism in Hepa1-6 cells. 84 genes contained in a commercially available fatty liver array were measured by qRT-PCR in Hepa1-6 cells transiently transfected and treated with FFA, as described in the legends of Figures 1 and 2. Results were clustered in four functional processes (carbohydrate metabolism, A; beta-oxidation, B; lipid metabolism, C; cholesterol transport, D), built on a number of complementary system analyses of biological pathways (see Supplemental Materials and Methods). Results of gene expression in each histogram are represented as % of the FFA-treated mock-transfected (blue), FFA-treated macroH2A1.1-overexpressing (green) or FFA-treated macroH2A1.2 – overexpressing (red) condition related to their respective untreated controls. Results are expressed as percentage of controls, means ± SEM of two independent experiments. *p<0.05.
Mentions: Moreover, data were clustered in undirected graphs, representing the above mentioned four processes of carbohydrate metabolism, beta-oxidation, lipid metabolism/transport, and cholesterol metabolism transport, where the thickness of the edges between genes correspond to the different degree of reliability of interaction, based on a number of heterogeneous data sources (protein domains, co-expression, co-localization, genetic interactions, pathways, physical and predicted interactions) (Figure 5A-D, S2A-D). In Hepa1-6, macroH2A1.1 over-expression induced, upon FFA treatment, dramatic changes in the expression of genes involved in carbohydrate metabolism when compared to macroH2A1.2 (downregulation of G6PC, GCK, MLXIPL, PDK4 and RBP4 and upregulation of PCK2 and GSK3B) or to FFA condition (upregulation of G6PC, GCK, MLXIPL and GSK3B and down-regulation of PCK2, PKLR and RBP4) (Figure 5A).

Bottom Line: The functional significance of this binding is unknown.Here we show that over-expression of macroH2A1.1, but not of macroH2A1.2, is able to protect hepatocytes against lipid accumulation.MacroH2A1.1 over-expressing cells display ameliorated glucose metabolism, reduced expression of lipidogenic genes and fatty acids content.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Sciences, Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.

ABSTRACT
Non-alcoholic-fatty-liver-disease (NAFLD) encompasses conditions associated to fat deposition in the liver, which are generally deteriorated during the aging process. MacroH2A1, a variant of histone H2A, is a key transcriptional regulator involved in tumorigenic processes and cell senescence, and featuring two alternatively splicing isoforms, macroH2A1.1 and macroH2A1.2. MacroH2A1.1 binds with high affinity O-acetyl ADP ribose, a small metabolite produced by the reaction catalysed by NAD+-dependent deacetylase SIRT1, whereas macroH2A1.2 is unable to do so. The functional significance of this binding is unknown. We previously reported that the hepatic levels of macroH2A1.1 and macroH2A1.2 are differentially expressed in mice models of NAFLD. Here we show that over-expression of macroH2A1.1, but not of macroH2A1.2, is able to protect hepatocytes against lipid accumulation. MacroH2A1.1 over-expressing cells display ameliorated glucose metabolism, reduced expression of lipidogenic genes and fatty acids content. SIRT1/macroH2A1.1-dependent epigenetic regulation of lipid metabolism may be relevant to NAFLD development.

Show MeSH
Related in: MedlinePlus