Obesity, non-alcoholic fatty liver disease and hepatocellular carcinoma: current status and therapeutic targets

Abstract

Obesity is a global epidemic and overwhelming evidence indicates that it is a risk factor for numerous cancers, including hepatocellular carcinoma (HCC), the third leading cause of cancer-related deaths worldwide. Obesity-associated hepatic tumorigenesis develops from nonalcoholic fatty liver disease (NAFLD), progressing to nonalcoholic steatohepatitis (NASH), cirrhosis and ultimately to HCC. The rising incidence of obesity is resulting in an increased prevalence of NAFLD and NASH, and subsequently HCC. Obesity represents an increasingly important underlying etiology of HCC, in particular as the other leading causes of HCC such as hepatitis infection, are declining due to effective treatments and vaccines. In this review, we provide a comprehensive overview of the molecular mechanisms and cellular signaling pathways involved in the pathogenesis of obesity-associated HCC. We summarize the preclinical experimental animal models available to study the features of NAFLD/NASH/HCC, and the non-invasive methods to diagnose NAFLD, NASH and early-stage HCC. Finally, since HCC is an aggressive tumor with a 5-year survival of less than 20%, we will also discuss novel therapeutic targets for obesity-associated HCC and ongoing clinical trials.

Keywords: animal models; hepatocellular carcinoma (HCC); metabolic dysfunction-associated fatty liver disease (MAFLD); nonalcoholic fatty liver disease (NAFLD); nonalcoholic steatohepatitis (NASH); obesity; therapeutic targets.

Figure 1

Summary of the mechanisms and serum markers of obesity-associated hepatocellular carcinoma (HCC) and current potential therapies. In the context of obesity, there is an increased risk of insulin resistant, gene variation, adipose tissue disfunction, epigenetic modification and intestinal microbiota imbalance, leading to lipotoxicity, endoplasmic reticulum (ER) stress, reactive oxygen species (ROS), inflammation and fibrosis, which ultimately progression to HCC. The molecular mechanisms involved in obesity-associated HCC including IGF, Wnt/β-catenin, JAK/STAT, PI3K/AKT, MAPK, AMPK, TLR, NF-κB and p53 signaling pathways. The serum markers and score system have been used in the diagnosis of NAFLD and NASH. Current potential therapies for obesity-associated HCC can be classified as insulin sensitizers, antioxidants as well as drugs against lipotoxicity, inflammation, fibrosis and apoptosis.