Molecular basis and mechanisms of progression of non-alcoholic steatohepatitis

Dipartimento di Medicina Interna and Centro di Ricerca, Trasferimento ed alta Formazione DenoTHE, University of Florence, Viale Morgagni 85, I-50134, Florence, Italy.
Trends in Molecular Medicine (Impact Factor: 9.45). 03/2008; 14(2):72-81. DOI: 10.1016/j.molmed.2007.12.003
Source: PubMed


Non-alcoholic steatohepatitis (NASH), a cause of cirrhosis and hepatocellular carcinoma, is characterized by fatty infiltration of the liver, inflammation, hepatocellular damage and fibrosis. Progress has been made in understanding the molecular and cellular mechanisms implicated in the pathogenesis of this condition, therefore, we here review recent developments regarding the basic mechanisms of NASH development. Accumulation of triglycerides in the hepatocytes is the result of increased inflow of free fatty acids and de novo lipogenesis. Steatosis leads to lipotoxicity, which causes apoptosis, necrosis, generation of oxidative stress and inflammation. The resulting chronic injury activates a fibrogenic response that leads eventually to end-stage liver disease. A better understanding of these mechanisms is crucial for the design of novel diagnostic and therapeutic strategies.

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Available from: Gianluca Tell, Apr 22, 2014
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    • "Despite large involvement in key human health crises, the pathogenesis of NAFLD is not completely understood; although the pathogenesis is considered to be multifactorial, including genetic, environmental and behavioral variables (3). As a result, current treatments for patients with fatty liver disease include lifestyle alterations and targeting the reduction of elevated lipolysis and high circulating free fatty acid (FFA) levels (4,5). Preventing increased circulating FFA levels in the liver, which can trigger a series of biological changes in hepatic lipid metabolism, may be an effective therapy for multiple stages of NAFLD (6). "
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    ABSTRACT: One of the most common causes of chronic liver disease, nonalcoholic fatty liver disease (NAFLD), is strongly associated with obesity and dysregulated insulin action in the liver. However, there are no pharmacological agents currently established for the treatment of NAFLD. A flowering plant in the Asteraceae family, Cirsium japonicum (CJ), exhibits a variety of pharmacological and antioxidative properties that promote hepatoprotection. In the present study, CJ ethanol extract was shown to reduce hepatic triglyceride (TG) and cholesterol accumulation. CJ significantly increased AMP-activated protein kinase (AMPK) phosphorylation in HepG2 hepatocytes and downregulated the level of the target genes, acetyl-CoA carboxylase and fatty acid synthase. In addition, CJ upregulated the expression of carnitine palmitoyltransferase-1, which is involved in fatty acid oxidation. The results of the present study indicated that the positive effects of CJ extract on high-fat diet-induced hepatic TG accumulation were mediated via the AMPK signaling pathway, indicating a potential target for the preventative treatment of NAFLD.
    Full-text · Article · Jul 2014 · Experimental and therapeutic medicine
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    • "NAFLD, which is present in up to 90% of all obese persons and in up to 70% of persons with type 2 diabetes, is a recognized risk factor for HCC, that may develop in NASH in the absence of cirrhosis [1]. However, the study of the molecular mechanisms linking steatosis development to chronic liver injury and HCC is hampered by the lack of adequate experimental models that often do not resemble the human situation [22], either are not associated to a significant development of chronic liver injury or lead to a cachectic phenotype that does not allow a long period of observation, as needed for carcinogenesis. In the CDAA model, mice develop steatosis in the absence of a high fat diet, mice continue to eat, do not reduce the appetite and the amount of calories introduced and weight changes are similar to control diet. "
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    ABSTRACT: NAFLD is the most common liver disease worldwide but it is the potential evolution to NASH and eventually to hepatocellular carcinoma (HCC), even in the absence of cirrhosis, that makes NAFLD of such clinical importance. Aim: we aimed to create a mouse model reproducing the pathological spectrum of NAFLD and to investigate the role of possible co-factors in promoting HCC. Methods: mice were treated with a choline-deficient L-amino-acid-defined-diet (CDAA) or its control (CSAA diet) and subjected to a low-dose i.p. injection of CCl4 or vehicle. Insulin resistance was measured by the euglycemic-hyperinsulinemic clamp method. Steatosis, fibrosis and HCC were evaluated by histological and molecular analysis. Results: CDAA-treated mice showed peripheral insulin resistance at 1 month. At 1-3 months, extensive steatosis and fibrosis were observed in CDAA and CDAA+CCl4 groups. At 6 months, equal increase in steatosis and fibrosis was observed between the two groups, together with the appearance of tumor. At 9 months of treatment, the 100% of CDAA+CCl4 treated mice revealed tumor versus 40% of CDAA mice. Insulin-like Growth Factor-2 (IGF-2) and Osteopontin (SPP-1) were increased in CDAA mice versus CSAA. Furthermore, Immunostaining for p-AKT, p-c-Myc and Glypican-3 revealed increased positivity in the tumors. Conclusions: the CDAA model promotes the development of HCC from NAFLD-NASH in the presence of insulin resistance but in the absence of cirrhosis. Since this condition is increasingly recognized in humans, our study provides a model that may help understanding mechanisms of carcinogenesis in NAFLD.
    Full-text · Article · May 2014 · PLoS ONE
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    • "Considering how this model is distinct from previous models of NAFLD is important and we find that the FFD-CCl4 rat model recreates in 8 weeks most histological lesions seen in the FFD mouse [20,47,48] with the exception of a change in serum glycemic/lipid profiles. This model has not shown features of metabolic syndrome thus this model does not exactly mimic human NAFLD. "
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    ABSTRACT: Background Non-alcoholic fatty liver disease (NAFLD) is defined as a spectrum of conditions ranging from hepatocellular steatosis to steatohepatitis and fibrosis, progressing to cirrhosis, which occur in the absence of excessive alcohol use. Several animal models capture aspects of NAFLD but are limited either in their representation of the disease stages or use for development of therapeutics due to the extended periods of time required to develop full histological features. Methods Here, we report the development of a novel rat model for NAFLD that addresses some of these limitations. We used a fast food diet (FFD) and a CCl4 micro dose (0.5 ml/kg B.wt) for 8 weeks in Wistar rats. Serological analyses, gene expression profiling and liver histology studies were conducted to investigate the development of steatosis, steatohepatitis and fibrosis in the FFD-CCl4 model when compared to the individual effects of a FFD or a micro dose of CCl4 in rats. Results The serum biochemical profile of the FFD-CCl4 model showed an increase in liver injury and fibrosis. This was also accompanied by a significant increase in liver triglycerides (TG), inflammation and oxidative stress. Importantly, we observed extensive fibrosis confirmed by: i) increased gene expression of fibrosis markers and, ii) moderate to severe collagen deposition seen as perisinusoidal and bridging fibrosis using H&E, Trichome and Sirius Red staining. Conclusions In summary, we find that the FFD-CCl4 rat model developed NAFLD histological features including, steatosis, inflammation and fibrosis in 8 weeks showing promise as a model that can be used to develop NAFLD therapeutics and liver anti-fibrotics.
    Full-text · Article · May 2014 · BMC Gastroenterology
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