Trends in Molecular Medicine
ReviewMolecular basis and mechanisms of progression of non-alcoholic steatohepatitis
Section snippets
Introduction to the problem
The term non-alcoholic steatohepatitis (NASH) (see Glossary; Box 1) was coined initially by Ludwig to describe histopathological findings typical of alcoholic liver disease in a group of patients without significant alcohol consumption [1]. NASH is observed in a subset of patients with non-alcoholic fatty liver disease (NAFLD), defined as fat accumulation in the liver exceeding 5–10% by weight. The clinical relevance of these conditions is related to the high prevalence of NAFLD in the general
Factors leading to fat accumulation in the liver
Accumulation of fat, mainly in the form of triglycerides, is the sine qua non for the development of NAFLD and NASH. The dynamics of lipid in the hepatocytes is both under control of distantly produced hormones (primarily insulin) and locally generated factors and represents the result of complex interactions among multiple cell types located in different tissues.
Mechanisms of damage in fat-laden hepatocytes
Fat accumulation in the cell might induce cytotoxicity either directly or through sensitization to other agents. Metabolic dysregulation, mitochondrial impairment and oxidative stress have a significant role in determining hepatocyte damage and result in profound changes in gene expression, leading ultimately to apoptosis and contributing to the inflammatory process [31].
NASH: inflammation and fibrosis
Together with hepatocyte damage, inflammation and fibrosis are the key features denoting the progression from simple steatosis to steatohepatitis. The molecular mechanisms of inflammation are largely cross-talking with those responsible for hepatocellular damage and fibrosis. In a large series of patients, hepatic inflammation or alanine aminotransferase (ALT) levels, as a proxy of necroinflammatory activity, are independent predictors of the fibrogenic progression of the disease. Finally,
Concluding remarks
An impressive amount of information has been accumulated in the past 5 years on all aspects of pathophysiology, molecular and cellular biology of NASH. Fatty infiltration of the liver is closely linked to IR and is considered a component of the metabolic syndrome. Ectopic fat infiltration might also lead to hepatocyte damage, a process defined ‘lipotoxicity’. Lipotoxicity and cell death are associated with activation of proinflammatory pathways, leading to leukocyte infiltration, damage
Conflicts of interest
The authors have no conflicts of interest to disclose in relation to the present paper.
Acknowledgements
Work in F.M.'s laboratory was supported by grants from the Italian Ministry of University and Research and from the University of Florence. C.T. was supported in part by a grant from Fondo Ricerca Stategica (FIST 2004), Fondo Studi Fegato-Onlus and Fondazione CRT. G.T. was supported in part by a grant from Progetto Ricerca Interesse Nazionale (PRIN) and from FIST (04). The authors gratefully acknowledge the contribution of the other members of the Fatty Liver Italian Network (FLIN): Stefano
Glossary
- Adipokines
- cytokines produced predominantly at the level of adipose tissue. Their action is both local (autocrine or paracrine) and distant (hormonal). Adipokines produced by visceral fat target the liver primarily through the portal circulation.
- De novo lipogenesis
- endogenous synthesis of FFAs within the liver.
- Hepatic stellate cells
- these surround the sinusoids in the normal liver, where they have a ‘quiescent’ state. After injury, these cells ‘activate’ and acquire features that are relevant for
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