Iron depletion therapy for the resolution of the HCV-induced steatohepatitis: development of new therapeutic strategy

Research project

Description

Hepatitis C virus (HCV) is estimated to infect approximately 170 million people worldwide, representing the most common cause of chronic liver disease. The morbidity and mortality associated with HCV infections are mainly attributable to the disease progression towards cirrhosis and, consequently, hepatocellular carcinoma.
The hepatic abnormal accumulations of fatty (steatosis) and iron are not only pathophysiological features of HCV infection but also key risk factors for the disease progression. Liver steatosis, in particular, occurs in about 50% or more of patients and the degree of hepatic fatty deposits has been correlated with the development of fibrosis, inflammation (steatohepatitis) and, consequently, cirrhosis. Although the risk factors underlying HCV-related steatosis are diverse (body mass index, type 2 diabetes, hypertriglyceridaemia, metabolic syndrome and HCV genotype), growing evidences are showing that hepatic iron overloading plays a causal role in the accumulation of fat in the liver. Among them, recent studies on HCV transgenic mice demonstrated that the viral induced hepatic iron overloading leads to the imbalance of lipid metabolism by both lipogenesis activation and reduced oxidation activity of fatty acids. Moreover, our recent in vivo and in vitro results demonstrated that HCV-induced iron accumulation also contributes to liver steatosis by the inhibition of very low density lipoproteins (VLDL) mediated fat export.
In light of these considerations it is conceivable that iron depletion (ID) could be a candidate as therapeutic strategy for the HCV-related steatohepatitis.

The present proposal aims to analyze the effects of ID on the hepatic lipid metabolism of transgenic mice with HCV-induced iron overloading. In particular, ID will be performed to address three specific tasks:
i) reduction of the hepatic fat accumulation;
ii) normalization of serum lipid profiling;
iii) analyze the VLDL structure.

Although the causal correlation between HCV-induced iron overloading and hepatic fat accumulation has been confirmed, the potential therapeutic role of iron depletion therapy for the resolution of clinical complications remains to be evaluated.
StatusActive
Effective start/end date1/1/12 → …

Funding

  • MIUR - FIRB

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Fatty Liver
Hepacivirus
Iron
Liver
Fats
Fibrosis
VLDL Lipoproteins
Lipid Metabolism
Transgenic Mice
Disease Progression
Infection
Hypertriglyceridemia
Liver Diseases
Hepatocellular Carcinoma
Body Mass Index
Chronic Disease
Fatty Acids
Genotype
Inflammation
Morbidity