Michela Borghesan

Redox homeostasis and epigenetics in non-alcoholic fatty liver disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD), an accumulation of intra-hepatic triglycerides that is often considered the hepatic manifestation of insulin resistance, is the most common cause of chronic liver disease in the Western countries with up to one third of the population affected. NAFLD is a spectrum of disturbances that encompasses various degrees of liver damage ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). NASH is characterized by hepatocellular injury/inflammation with or without fibrosis. The individuals with NAFLD develop NASH in 10% of the cases, and are also at risk of developing hepatocellular carcinoma (HCC). Epigenetic mechanisms of nuclear chromatin remodeling, such as DNA methylation, post-translational modifications of histones, and incorporation of histone variants into the chromatin are increasingly recognized as crucial factors in the pathophysiology of NAFLD. NAFLD is often accompanied by oxidative stress: reactive oxygen species (ROS) are implicated in altered reduction/oxidation (redox) reactions that attack cellular macromolecules and are detected in the liver of patients and animal models of NAFLD. In this review, we summarize recent knowledge advancements in the hepatic epigenetic and redox mechanisms, and their possible links, involved in the pathogenesis and treatment of NAFLD.

Histone macroH2A1.2 promotes metabolic health and leanness by inhibiting adipogenesis

BackgroundObesity has tremendous impact on the health systems. Its epigenetic bases are unclear. MacroH2A1 is a variant of histone H2A, present in two alternatively exon-spliced isoforms macroH2A1.1 and macroH2A1.2, regulating cell plasticity and proliferation, during pluripotency and tumorigenesis. Their role in adipose tissue plasticity is unknown.ResultsHere, we show evidence that macroH2A1.1 protein levels in the visceral adipose tissue of obese humans positively correlate with BMI, while macroH2A1.2 is nearly absent. We thus introduced a constitutive GFP-tagged transgene for macroH2A1.2 in mice, and we characterized their metabolic health upon being fed a standard chow diet or a high fat diet. Despite unchanged food intake, these mice exhibit lower adipose mass and improved glucose metabolism both under a chow and an obesogenic diet. In the latter regimen, transgenic mice display smaller pancreatic islets and significantly less inflammation. MacroH2A1.2 overexpression in the mouse adipose tissue induced dramatic changes in the transcript levels of key adipogenic genes; genomic analyses comparing pre-adipocytes to mature adipocytes uncovered only minor changes in macroH2A1.2 genomic distribution upon adipogenic differentiation and suggested differential cooperation with transcription factors. MacroH2A1.2 overexpression markedly inhibited adipogenesis, while overexpression of macroH2A1.1 had opposite effects.ConclusionsMacroH2A1.2 is an unprecedented chromatin component powerfully promoting metabolic health by modulating anti-adipogenic transcriptional networks in the differentiating adipose tissue. Strategies aiming at enhancing macroH2A1.2 expression might counteract excessive adiposity in humans.

DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy-Induced Senescence to Promote Hepatocellular Carcinoma Progression

Aging is a major risk factor for progression of liver diseases to hepatocellular carcinoma (HCC). Cellular senescence contributes to age-related tissue dysfunction, but the epigenetic basis underlying drug-induced senescence remains unclear. macroH2A1, a variant of histone H2A, is a marker of senescence-associated heterochromatic foci that synergizes with DNA methylation to silence tumor-suppressor genes in human fibroblasts. In this study, we investigated the relationship between macroH2A1 splice variants, macroH2A1.1 and macroH2A1.2, and liver carcinogenesis. We found that protein levels of both macroH2A1 isoforms were increased in the livers of very elderly rodents and humans, and were robust immunohistochemical markers of human cirrhosis and HCC. In response to the chemotherapeutic and DNA-demethylating agent 5-aza-deoxycytidine (5-aza-dC), transgenic expression of macroH2A1 isoforms in HCC cell lines prevented the emergence of a senescent-like phenotype and induced synergistic global DNA hypomethylation. Conversely, macroH2A1 depletion amplified the antiproliferative effects of 5-aza-dC in HCC cells, but failed to enhance senescence. Senescence-associated secretory phenotype and whole-transcriptome analyses implicated the p38 MAPK/IL8 pathway in mediating macroH2A1-dependent escape of HCC cells from chemotherapy-induced senescence. Furthermore, chromatin immunoprecipitation sequencing revealed that this hepatic antisenescence state also required active transcription that could not be attributed to genomic occupancy of these histones. Collectively, our findings reveal a new mechanism by which drug-induced senescence is epigenetically regulated by macroH2A1 and DNA methylation and suggest macroH2A1 as a novel biomarker of hepatic senescence that could potentially predict prognosis and disease progression.

Caloric restriction and aging stem cells: The stick and the carrot?

Adult tissue stem cells have the ability to adjust to environmental changes and affect also the proliferation of neighboring cells, with important consequences on tissue maintenance and regeneration. Stem cell renewal and proliferation is strongly regulated during aging of the organism. Caloric restriction is the most powerful anti-aging strategy conserved throughout evolution in the animal kingdom. Recent studies relate the properties of caloric restriction to its ability in reprogramming stem-like cell states and in prolonging the capacity of stem cells to self-renew, proliferate, differentiate, and replace cells in several adult tissues. However this general paradigm presents with exceptions. The scope of this review is to highlight how caloric restriction impacts on diverse stem cell compartments and, by doing so, might differentially delay aging in the tissues of lower and higher organisms.

Histone variants and lipid metabolism

Within nucleosomes, canonical histones package the genome, but they can be opportunely replaced with histone variants. The incorporation of histone variants into the nucleosome is a chief cellular strategy to regulate transcription and cellular metabolism. In pathological terms, cellular steatosis is an abnormal accumulation of lipids, which reflects impairment in the turnover of triacylglycerols, affecting any organ but mainly the liver. The present review aims to summarize the experimental evidence for histone variant functions in lipid metabolism.

P235 SYSTEMS ANALYSIS OF NAFLD GENE EXPRESSION UNVEILS A PROTECTIVE ROLE FOR macroH2A1.1 IN HEPATOCYTE AGAINST LIPID ACCUMULATION

kcal/100 g) for 12 weeks. Control mice consumed normal laboratory chaw (360 kcal/100 g). Anti-HBs production due to immunization with HBsAg-based vaccine was evaluated in vivo. HBsAg-specific T cell proliferation and functional capacities of MDSC and DC were evaluated in vitro. Results: In spite of exhibiting an inflammatory hepatic mucosa (increased serum ALT and hepatic inflammation) and fatty acids were compared to control mice (P < 0.05). the levels of anti-HBs and HBsAg-specific T lymphocyte proliferation were significantly lower in NAFLD mice compared to control mice (p < 0.01). The proliferation of T and B lymphocytes was increased in NAFLD mice due to stimulation with polyclonal immune modulators (concanavalin A and lipopolysaccharides). However, the capacity of DC of NAFLD mice to process and present HBsAg were significantly lower than those of control mice (p < 0.05). In addition, impaired DC functions of NAFLD mice were further exacerbated in presence of MDSC of NAFDL mice. Conclusions: Impaired antigen-specific immunity of NAFLD subjects to vaccine in spite of inflammatory mucosal milieu seems to be related to distorted antigen presenting capacity of DC and suppressor capacity of MDSC.