Neutral Sphingomyelinase 2 Inhibition Limits Hepatic Steatosis and Inflammation
Fatema Al‐RashedHossein ArefanianAshraf Al MadhounFatemah BahmanSardar SindhuHalemah AlSaeedTexy JacobReeby ThomasAreej Al-RoubFawaz AlzaïdMd. Zubbair MalikRasheeba NizamThangavel Alphonse ThanarajFahd Al‐MullaYusuf A. HannunRasheed Ahmad
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Abstract:
Non-alcoholic fatty liver disease (NAFLD) is manifested by hepatic steatosis, insulin resistance, hepatocyte death, and systemic inflammation. Obesity induces steatosis and chronic inflammation in the liver. However, the precise mechanism underlying hepatic steatosis in the setting of obesity remains unclear. Here, we report studies that address this question. After 14 weeks on a high-fat diet (HFD) with high sucrose, C57BL/6 mice revealed a phenotype of liver steatosis. Transcriptional profiling analysis of the liver tissues was performed using RNA sequencing (RNA-seq). Our RNA-seq data revealed 692 differentially expressed genes involved in processes of lipid metabolism, oxidative stress, immune responses, and cell proliferation. Notably, the gene encoding neutral sphingomyelinase, SMPD3, was predominantly upregulated in the liver tissues of the mice displaying a phenotype of steatosis. Moreover, nSMase2 activity was elevated in these tissues of the liver. Pharmacological and genetic inhibition of nSMase2 prevented intracellular lipid accumulation and TNFα-induced inflammation in in-vitro HepG2-steatosis cellular model. Furthermore, nSMase2 inhibition ameliorates oxidative damage by rescuing PPARα and preventing cell death associated with high glucose/oleic acid-induced fat accumulation in HepG2 cells. Collectively, our findings highlight the prominent role of nSMase2 in hepatic steatosis, which could serve as a potential therapeutic target for NAFLD and other hepatic steatosis-linked disorders.Keywords:
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Introduction: Liver grafts with limited steatosis are currently used for liver transplantation, but the natural history of graft steatosis is not well known. Project Aims or Questions: This program evaluation aimed at assessing changes of steatosis after liver transplantation. Design: A retrospective chart review was performed assessing presence and severity of steatosis in the liver explant and in time zero donor graft biopsies carried out at the time-point of liver transplantation on histopathology and on imaging one year thereafter in 30 well characterized patients. Results: Ten patients (33%) showed steatosis on explant. Time zero biopsy revealed steatosis in 18 grafts (60%) and no steatosis in 12 (40%). One year after transplantation, 8 patients (27%) had steatosis and 22 patients (63%) had none. Fourteen patients (47%) showed changes in steatosis: 12 showed resolution and 2 showed de novo steatosis. Explant macrovesicular steatosis was associated with presence of steatosis 1 year after transplantation (binary logistic regression model, p = 0.014), but not macrovesicular steatosis in the donor graft at time-point of transplantation. Conclusion: Resolution of graft steatosis was frequent. Presence of steatosis in the recipient's liver, but not graft steatosis, was a risk factor for steatosis 1 year after transplantation. Factors related to the recipient seem to prevail over donor-related factors in determining the persistence or de novo appearance of steatosis after liver transplantation.
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Two distinct forms of hepatocellular steatosis can be seen in patients with chronic hepatitis C virus (HCV) infection. Classical metabolic risk factors for hepatocellular steatosis account for the vast majority of cases of steatosis in patients infected by non-genotype 3 HCV strains. In contrast, in patients infected by HCV genotype 3, steatosis is generally induced by the virus itself through a direct cytopathic effect, the mechanisms of which remain debated. Mixed forms of steatosis can also be seen in HCV genotype 3-infected patients with metabolic risk factors. Hepatocellular steatosis appears to be associated with more rapid progression of hepatic fibrosis. However, it is unclear whether this association is due to steatosis itself, or rather to metabolic and host factors that promote steatosis and fibrosis concomitantly. This review discusses current knowledge of HCV-induced steatosis and its relation to chronic HCV-associated liver disease.
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Fatty liver disease is a common chronic liver disease which is mainly induced by abnormal lipid metabolism. To find out the effect of GP73 on lipid metabolism in the liver, we constructed a high GP73 expression liver model through a tail vein injection of AAV-GP73 into eight-week-old C57BL/6J mice. Liver lipid metabolomics analysis showed that lipids in the liver of mice, especially the triglycerides, were significantly increased. In addition, kyoto encyclopedia of genes and genomes enrichment analysis showed that GP73 altered lipid metabolites profile that may further disturb many signaling pathways related to cellular metabolism. The diseases linked to type II diabetes, non-alcoholic fatty liver disease (NAFLD) and choline metabolism in cancer cells were more likely to be dysregulated. Thus, GP73 may induce fatty liver by regulating lipid metabolism and promoting lipid accumulation in the liver.
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The liver is an essential metabolic organ. In addition to metabolizing glucose and lipids, hepatocytes also secrete various cytokines that modulate both hepatocyte metabolism and liver inflammation. Hepatocyte injury and death and liver inflammation are the major contributors to liver diseases, including nonalcoholic steatohepatitis (NASH). Anatomic locations have a profound effect on hepatocyte metabolism, and liver zonation describes the metabolic heterogeneity of hepatocytes along the portovenous axis. However, it is unclear whether hepatocyte heterogeneity is affected by intrinsic factors and whether dietary fat, a risk factor for NASH, has distinct detrimental effects on different hepatocyte subpopulations. Here, we showed that mouse livers contained both high-lipid and low-lipid subpopulations of hepatocytes. The high-lipid subpopulation was more susceptible to injury and apoptosis and produced more proinflamatrory cytokines after treatment with endotoxin and saturated fatty acids. Dietary fat consumption further increased fatty acid uptake, intracellular lipid levels, hepatocyte injury and death, and the expression of proinflammatory cytokines in the high-lipid subpopulation. In contrast, dietary fat slightly increased lipid levels, cell death, and expression of proinflammatory cytokines in the low-lipid subpopulation. The low-lipid subpopulation produced more glucose. Fat consumption further activated the gluconeogenic program in the low-lipid, but not the high-lipid, subpopulations. These data suggest that intracellular lipid content is a key intrinsic determinant for hepatocyte heterogeneity of metabolic, inflammatory, and survival states.
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Abstract Background: Steatosis is diagnosed on the basis of the macroscopic aspect of the liver evaluated by the surgeon at the time of organ extraction or by means of a frozen biopsy. Aim: In the present study, the applicability of laser‐induced fluorescence (LIF) spectroscopy was investigated as a method for the diagnosis of different degrees of steatosis experimentally induced in rats. Material and methods: Rats received a high‐lipid diet for different periods of time. The animals were divided into groups according to the degree of induced steatosis diagnosis by histology. The concentration of fat in the liver was correlated with LIF by means of the steatosis fluorescence factor (SFF). Results: The histology classification, according to liver fat concentration was, Severe Steatosis, Moderate Steatosis, Mild Steatosis and Control (no liver steatosis). Fluorescence intensity could be directly correlated with fat content. It was possible to estimate an average of fluorescence intensity variable by means of different confidence intervals ( P =95%) for each steatosis group. SFF was significantly higher in the Severe Steatosis group ( P <0.001) compared with the Moderate Steatosis, Mild Steatosis and Control groups. Conclusion: The various degrees of steatosis could be directly correlated with SFF. LIF spectroscopy proved to be a method capable of identifying the degree of hepatic steatosis in this animal model, and has the potential of clinical application for non‐invasive evaluation of the degree of steatosis.
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AIMS To evaluate the frequency and the severity of hepatic steatosis in chronic hepatitis C patients, to identify the associated factors with the presence of steatosis and to determine the relationship between the presence of steatosis and severity of hepatic fibrosis. METHODS Lecture of hepatic biopsies was performed blindly by the same histopathologist, using the METAVIR grading. Hepatic steatosis was graded as macrovacuolar or microvesicular. Steatosis was considered as mild, moderate and severe if involving less than 10%, between 10 and 30% and more than 30% of hepatocytes respectively. RESULTS One hundred and nine patients were studied. Determination of the virus genotype was performed in 59 patients, with 93% of genotype 1. Significant fibrosis was noted in 72 patients (66%). Hepatic steatosis was detected in 53 cases (49%): Mild in 32 cases (30%), moderate in 9 cases (8%) and severe in 12 cases (11%). In univariate analysis, associated factors with steatosis are age more than 50 years, weight more than 65 kg, body mass index more than 25 kg/m2, ASAT levels more than 80 UI/l and ALAT levels more than 100 UI/l. In multivariate analysis, only body mass index more than 25 kg/m2 is associated with the presence of steatosis (p=0.02 OR [95%CI]: 3.37 [1.19-9.53]). Significant fibrosis was more frequently detected in patients with steatosis compared to patients without steatosis (42/53: 80% vs 30/56: 54%; p=0.004). CONCLUSION Hepatic steatosis is frequent in chronic viral hepatitis C. In our Tunisian population, steatosis is associated with body mass index and not with virological factors.
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The relationship between steatosis and angiogenesis in chronic hepatitis C (CHC) is unclear.The aim was to explain whether liver steatosis presence and its extent are associated with the number of new-formed blood vessels in lobules and portal tracts in CHC. 72 CHC patients infected with viral genotype 1b, 35 of whom had steatosis were evaluated. Monoclonal antibody anti-CD34 was used to identify new-formed blood vessels.Patients with steatosis had a significantly more advanced stage of fibrosis (p = 0.002) and higher inflammatory activity grade (p = 0.062). CD34 expression in portal tracts (CD34pt), lobules and fibrous septa (CD34lfs) and total (CD34) were significantly higher in patients with steatosis (p = 0.034; p = 0.021; p = 0.023, respectively). CD34, CD34pt and CD34lfs differed significantly between patients with various steatosis grade (p = 0.006; p = 0.009; p = 0.013, respectively). CD34 and CD34pt differed significantly between each steatosis grade whereas CD34lfs between grade 1 and 3. Fibrosis stage and inflammatory grade were positively associated with steatosis extent (p = 0.015; p = 0.003, respectively).Our observations suggest that extensive steatosis of liver parenchyma in CHC patients is associated with formation of new blood vessels in lobules and portal tracts. Understanding the relationship between steatosis, fibrosis and angiogenesis is therefore of great importance for the introduction of new therapeutic approaches and in the evaluation of CHC progression.
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