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Abstract
Nonalcoholic steatohepatitis (NASH) is becoming a public health problem worldwide. While the number of research studies on NASH progression rises every year, sometime their findings are controversial. To identify the most important and commonly described findings related to NASH progression, we used an original bioinformatics, integrative, text-mining approach that combines PubMed database querying and available gene expression omnibus dataset. We have identified a signature of 25 genes that are commonly found to be dysregulated during steatosis progression to NASH and cancer. These genes are implicated in lipid metabolism, insulin resistance, inflammation, and cancer. They are functionally connected, forming the basis necessary for steatosis progression to NASH and further progression to hepatocellular carcinoma (HCC). We also show that five of the identified genes have genome alterations present in HCC patients. The patients with these genes associated to genome alteration are associated with a poor prognosis. In conclusion, using an integrative literature- and data-mining approach, we have identified and described a canonical pathway underlying progression of NASH. Other parameters (e.g., polymorphisms) can be added to this pathway that also contribute to the progression of the disease to cancer. This work improved our understanding of the molecular basis of NASH progression and will help to develop new therapeutic approaches.
Highlights
Liver is a major integrator of metabolism and plays a key role in lipid metabolism including fatty acid oxidation, lipogenesis, cholesterol synthesis, and production of triglycerides and lipoproteins [1,2,3]
A variety of conditions result in dysregulation of lipid metabolism which leads to fat accumulation in the liver and to nonalcoholic fatty liver disease (NAFLD)
We identified 25 genes implicated in the progressions of steatosis to nonalcoholic steatohepatitis (NASH), genes implicated in lipid metabolism, inflammation processes, and five more genes implicated in cancer development
Summary
Liver is a major integrator of metabolism and plays a key role in lipid metabolism including fatty acid oxidation, lipogenesis, cholesterol synthesis, and production of triglycerides and lipoproteins [1,2,3]. A variety of conditions result in dysregulation of lipid metabolism which leads to fat accumulation in the liver and to nonalcoholic fatty liver disease (NAFLD). NAFLD is a pathological condition, exhibiting a wide range of lesions starting with the accumulation of lipid droplets in the liver known as hepatic steatosis or nonalcoholic fatty liver (NAFL). Our previous studies revealed alterations in homeostasis of triglycerides, cholesterol, phospholipids, and long-chain fatty acids during the progression of NASH [19,20]. An increase in lipid species such as saturated fatty acids and phospholipids, as well as disturbances in ceramide-signaling or alterations in cholesterol content are associated with pro-inflammatory and pro-apoptotic properties [16,19,20,29,30,31,32,33,34]. Alterations in lipid metabolism during NASH progression have been associated with gene expression changes and single nucleotide polymorphisms in genes involved in lipid metabolism and in genes associated with inflammatory and cancerous processes [18,19,28,35,36,37,38,39,40,41,42,43,44,45,46]
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