The role of the gaseous signaling molecule hydrogen sulfide in chronic liver disease:Special emphasis on non-alcoholic fatty liver disease

Due to the high world-wide prevalence of obesity, non-alcoholic fatty liver disease (NAFLD) has become one of the major chronic liver diseases in the world. NAFLD covers a range of disease stages and in its chronic stages is always accompanied by co-morbidities, such as obesity, insulin resistance (IR), metabolic syndrome and type 2 diabetes (T2D). NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis and subsequently cirrhosis and hepatocellular carcinoma (HCC). Many drugs have been proposed to treat NAFLD, however, none of them showed high efficacy, leaving a change of lifestyle in the early phase or liver transplantation at the late stages as the only effective options to treat of NAFLD. It is vital to understand the complexity of the disease and to consider the underlying mechanisms in each stage. In the current thesis we used primary rat hepatocytes and hepatic stellate cells (HSCs) to study the role of hydrogen sulfide (H2S) in NAFLD. In addition, we used a large cohort (PREVEND database, n=5562) to validate our experimental findings in a more clinical setting. We used primary rat hepatocytes to study simple steatosis and primary rat stellate cells to investigate fibrosis. In these experimental models, we investigated the role of hydrogen sulfide as well as the natural coumarin derivative esculetin. Free thiols (R-SH) were measured in serum samples of a large cohort to investigate the relation between clinical NAFLD and thiol status

Hepatic Stellate Cell Senescence in Liver Fibrosis:Characteristics, Mechanisms and Perspectives

Myofibroblasts play an important role in fibrogenesis. Hepatic stellate cells are the main precursors of myofibroblasts. Cellular senescence is the terminal cell fate in which proliferating cells undergo irreversible cell cycle arrest. Senescent hepatic stellate cells were identified in liver fibrosis. Senescent hepatic stellate cells display decreased collagen production and proliferation. Therefore, induction of senescence could be a protective mechanism against progression of liver fibrosis and the concept of therapy-induced senescence has been proposed to treat liver fibrosis. In this review, characteristics of senescent hepatic stellate cells and the essential signaling pathways involved in senescence are reviewed. Furthermore, the potential impact of senescent hepatic stellate cells on other liver cell types are discussed. Senescent cells are cleared by the immune system. The persistence of senescent cells can remodel the microenvironment and interact with inflammatory cells to induce aging-related dysfunction. Therefore, senolytics, a class of compounds that selectively induce death of senescent cells, were introduced as treatment to remove senescent cells and consequently decrease the disadvantageous effects of persisting senescent cells. The effects of senescent hepatic stellate cells in liver fibrosis need further investigation

Hydrogen sulfide stimulates activation of hepatic stellate cells through increased cellular bio-energetics

Hepatic fibrosis is caused by chronic inflammation and characterized as the excessive accumulation of extra cellular matrix (ECM) by activated hepatic stellate cells (HSCs). Gasotransmitters like NO and CO are known to modulate inflammation and fibrosis, however, little is known about the role of the gasotransmitter hydrogen sulfide (H2S) in liver fibrogenesis and stellate cell activation. Endogenous H2S is produced by the enzymes cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CTH) and 3-mercaptopyruvate sulfur transferase (MPST) [1]. The aim of this study was to elucidate the role of endogenously produced and/or exogenously administered H2S on rat hepatic stellate cell activation and fibrogenesis. Primary rat HSCs were culture-activated for 7 days and treated with different H2S releasing donors (slow releasing donor GYY4137, fast releasing donor NaHS) or inhibitors of the H2S producing enzymes CTH and CBS (DL-PAG, AOAA). The main message of our study is that mRNA and protein expression level of H2S synthesizing enzymes are low in HSCs compared to hepatocytes and Kupffer cells. However, H2S promotes hepatic stellate cell activation. This conclusion is based on the fact that production of H2S and mRNA and protein expression of its producing enzyme CTH are increased during hepatic stellate cell activation. Furthermore, exogenous H2S increased HSC proliferation while inhibitors of endogenous H2S production reduce proliferation and fibrotic makers of HSCs. The effect of H2S on stellate cell activation correlated with increased cellular bioenergetics. Our results indicate that the H2S generation in hepatic stellate cells is a target for anti-fibrotic intervention and that systemic interventions with H2S should take into account cell-specific effects of H2S.</p

a-1 Adrenergic receptor antagonist doxazosin reverses hepatic stellate cells activation via induction of senescence

BACKGROUND: Activated hepatic stellate cells (aHSCs) are the main effector cells during liver fibrogenesis. α-1 adrenergic antagonist doxazosin (DX) was shown to be anti-fibrotic in an in vivo model of liver fibrosis (LF), but the mechanism remains to be elucidated. Recent studies suggest that reversion of LF can be achieved by inducing cellular senescence characterized by irreversible cell-cycle arrest and acquisition of the senescence-associated secretory phenotype (SASP). AIM: To elucidate the mechanism of the anti-fibrotic effect of DX and determine whether it induces senescence. METHODS: Primary culture-activated rat HSCs were used. mRNA and protein expression were measured by qPCR and Western blot, respectively. Cell proliferation was assessed by BrdU incorporation and xCelligence analysis. TGF-β was used for maximal HSC activation. Norepinephrine (NE), PMA and m-3M3FBS were used to activate alpha-1 adrenergic signaling. RESULTS: Expression of Col1α1 was significantly decreased by DX (10 µmol/L) at mRNA (-30 %) and protein level (-50 %) in TGF-β treated aHSCs. DX significantly reduced aHSCs proliferation and increased expression of senescence and SASP markers. PMA and m-3M3FBS reversed the effect of DX on senescence markers. CONCLUSION: Doxazosin reverses the fibrogenic phenotype of aHSCs and induces the senescence phenotype

Oxidative stress is associated with suspected non-alcoholic fatty liver disease and all-cause mortality in the general population

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation, inflammation and an imbalanced redox homeostasis. We hypothesized that systemic free thiol levels, as a proxy of systemic oxidative stress, are associated with NAFLD. Methods: Protein-adjusted serum free thiol concentrations were determined in participants from the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort study (n = 5562). Suspected NAFLD was defined by the Fatty Liver Index (FLI ≥ 60) and Hepatic Steatosis Index (HSI > 36). Results: Protein-adjusted serum free thiols were significantly reduced in subjects with FLI ≥ 60 (n = 1651). In multivariable logistic regression analyses, protein-adjusted serum free thiols were associated with NAFLD (FLI ≥ 60) (OR per doubling of concentration: 0.78 [95% CI 0.64-0.96], P =.016) even when adjusted for potential confounding factors, including systolic blood pressure, diabetes, current smoking, use of alcohol and total cholesterol (OR 0.80 [95% CI 0.65-0.99], P =.04). This association lost its significance (OR 0.94 [95% CI 0.73-1.21], P =.65) after additional adjustment for high-sensitive C-reactive protein. Stratified analyses showed significantly differential associations of protein-adjusted serum free thiol concentrations with suspected NAFLD for gender (P <.02), hypertension (P <.001) and hypercholesterolemia (P <.003). Longitudinally, protein-adjusted serum free thiols were significantly associated with the risk of all-cause mortality in subjects with NAFLD (FLI ≥ 60) (HR 0.27 [95% CI 0.17-0.45], P <.001). Conclusion: Protein-adjusted serum free thiol levels are reduced and significantly associated with all-cause mortality in subjects with suspected NAFLD. Quantification of free thiols may be a promising, minimally invasive strategy to improve detection of NAFLD and associated risk of all-cause mortality in the general population

Estimating the Impacts of Hospitals’ Organisational and Geographical Characteristics on the Adoption of Health Information Technology in Mongolian Hospitals

Background. The adoption of health information technology (HIT) is an important measure for improving healthcare quality and safety, which is affected by many hospital factors, but it has not yet been estimated in the Mongolian hospital sectors. This study examines how hospitals’ organisational and geographical characteristics influence the adoption of HIT in Mongolian tertiary and secondary care hospitals. Methods. А cross-sectional study involving the executive directors and medical equipment engineers was conducted in 39 hospitals. Data acquired from questionnaires are (1) hospitals’ organisational and geographical characteristics, including bed-size capacity, ownership type, status, and location of the hospitals, and (2) the adoption rate of HIT, and its categories are based on the Health Information and Management Systems Society’s classification (2002). The dependent variable was measured as numbers and the rate of HIT programs adopted clinical, administrative, and strategic information technologies (IT). A regression analysis was used to estimate the factors of impact on the adoption of clinical, administrative, and strategic IT. Results. We found a concerning relationship between the characteristics and adoption of HITs. On average, the number of HIT programs adopted was 18, covering nine clinical IT programs, six administrative IT programs, and three strategic IT programs. The adoption rate of overall HIT was 33.29% in the hospitals. In regression analysis, the organisational and geographical characteristics’ impact and HIT adoption of hospitals was positively associated with large bed-size (clinical IT: β = 0.256, P<0.001; administrative IT: β = 0.3654, P<0.001; strategic IT: β = 0.0006, P<0.001), for-profit (strategic IT: β = 0.1995, P<0.01), teaching (clinical IT: β = 0.2560, P<0.05; administrative IT: β = 0.1985, P<0.05; strategic IT: β = 0.2236, P<0.01), and urban location (clinical IT: β = 0.2840, P<0.001, administrative IT: β = 0.2256, P<0.01; strategic IT: β = 0.2256, P<0.001). Conclusion. Our study found that the HIT adoption rate in Mongolia is poor, and its adoption is mainly positively associated with bed-size capacity, status, and location of the hospitals. Also, we found that the ownership type is partially affected HIT adoption