Abstract
Non-alcoholic fatty liver disease (NAFLD) and its advanced complication, non-alcoholic steatohepatitis (NASH), have become leading causes of hepatocellular carcinoma (HCC) worldwide. In this review, we discuss the role of metabolic, gut microbial, immune and endocrine mediators which promote the progression of NAFLD to HCC. In particular, this progression involves multiple hits resulting from lipotoxicity, oxidative stress, inhibition of hepatic autophagy and inflammation. Furthermore, dysbiosis in the gut associated with obesity also promotes HCC via induction of proinflammatory cytokines and Toll like receptor signalling as well as altered bile metabolism. Additionally, compromised T-cell function and impaired hepatic hormonal action promote the development of NASH-associated HCC. Lastly, we discuss the current challenges involved in the diagnosis and treatment of NAFLD/NASH-associated HCC.
Highlights
Hepatocellular carcinoma (HCC) is the primary form of liver cancer and is a leading cause of cancerrelated mortality worldwide[1]
Chronic damage to liver metabolism caused by alcohol and poor nutrition leads to alcoholic liver disease that can co-exist with non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatistis (NASH), and thereby increases both the progression of NAFLD and the risk for NAFLD/NASH-associated HCC[2,3]
The association of obesity, high-fat diet and diabetes to NAFLD/NASH and its progression to HCC suggests the existence of a molecular link between energy metabolism and cell cycle control in the hepatocytes, which may be a key mechanism driving the progression of NASH to HCC
Summary
Hepatocellular carcinoma (HCC) is the primary form of liver cancer and is a leading cause of cancerrelated mortality worldwide[1]. The high production of ROS causes mitochondrial damage, lipid peroxidation and low-density lipoprotein oxidation culminating into inflammation, activation of hepatic stellate cells (HSCs) leading to fibrogenesis, necrosis, cirrhosis and HCC[39]. Deregulated or insufficient responses to ER stress in liver may lead to lipid accumulation, insulin resistance, inflammation and apoptosis, all of which play important roles in the pathogenesis of NAFLD[40].
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