Molecular Mechanisms: Connections between Nonalcoholic Fatty Liver Disease, Steatohepatitis and Hepatocellular Carcinoma

Int J Mol Sci. 2020 Feb 23;21(4):1525. doi: 10.3390/ijms21041525.


Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), causes hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The patatin-like phospholipase-3 (PNPLA3) I148M sequence variant is one of the strongest genetic determinants of NAFLD/NASH. PNPLA3 is an independent risk factor for HCC among patients with NASH. The obesity epidemic is closely associated with the rising prevalence and severity of NAFLD/NASH. Furthermore, metabolic syndrome exacerbates the course of NAFLD/NASH. These factors are able to induce apoptosis and activate immune and inflammatory pathways, resulting in the development of hepatic fibrosis and NASH, leading to progression toward HCC. Small intestinal bacterial overgrowth (SIBO), destruction of the intestinal mucosa barrier function and a high-fat diet all seem to exacerbate the development of hepatic fibrosis and NASH, leading to HCC in patients with NAFLD/NASH. Thus, the intestinal microbiota may play a role in the development of NAFLD/NASH. In this review, we describe recent advances in our knowledge of the molecular mechanisms contributing to the development of hepatic fibrosis and HCC in patients with NAFLD/NASH.

Keywords: HCC; HSD17B13; NAFLD; NASH; PNPLA3; dysbiosis; metabolic syndrome; microbiota; obesity.

Publication types

  • Review

MeSH terms

  • 17-Hydroxysteroid Dehydrogenases / metabolism
  • Animals
  • Apoptosis
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / metabolism*
  • Diet, High-Fat
  • Disease Progression
  • Dysbiosis / metabolism
  • Fatty Liver / genetics
  • Fatty Liver / immunology
  • Fatty Liver / metabolism*
  • Fibrosis
  • Gastrointestinal Microbiome / physiology
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Intestinal Mucosa
  • Lipase / genetics
  • Lipase / metabolism*
  • Liver / pathology
  • Liver Cirrhosis / immunology
  • Liver Cirrhosis / pathology
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Metabolic Syndrome / genetics
  • Metabolic Syndrome / metabolism
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / immunology
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Obesity
  • Prevalence
  • Risk Factors


  • Membrane Proteins
  • 17-Hydroxysteroid Dehydrogenases
  • HSD17B13 protein, human
  • Lipase
  • adiponutrin, human