Nonalcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: Current Issues and Future Perspectives in Preclinical and Clinical Research

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a continuum of liver abnormalities often starting as simple steatosis and to potentially progress into nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma. Because of its increasing prevalence, NAFLD is becoming a major public health concern, in parallel with a worldwide increase in the recurrence rate of diabetes and metabolic syndrome. It has been estimated that NASH cirrhosis may surpass viral hepatitis C and become the leading indication for liver transplantation in the next decades. The broadening of the knowledge about NASH pathogenesis and progression is of pivotal importance for the discovery of new targeted and more effective therapies; aim of this review is to offer a comprehensive and updated overview on NAFLD and NASH pathogenesis, the most recommended treatments, drugs under development and new drug targets. The most relevant in vitro and in vivo models of NAFLD and NASH will be also reviewed, as well as the main molecular pathways involved in NAFLD and NASH development.

Keywords: hepatocellular carcinoma; metabolic syndrome; non-alcoholic fatty liver disease; steatohepatitis; steatosis.

Figure 1

Non-alcoholic steatohepatitis (NASH) pathogenesis. Free fatty acids have a key role in the pathogenesis of NASH. Free fatty acids primarily originate from lipolysis of triglycerides in adipose tissue; insulin resistance may contribute to NASH through a lipolysis dysregulation. The other major contributor to the free fatty acid liver accumulation is de novo lipogenesis (DNL), resulting from hepatocyte-mediated conversion of fructose to fatty acids. Fatty acids, in hepatocytes, are directed toward mitochondrial beta-oxidation or re-esterification to form triglycerides. Triglycerides can be exported into the blood as VLDL or stored in lipid droplets. When the beta-oxidation or triglyceride conversion of fatty acids is overwhelmed, lipotoxicity occurs, leading to ER stress, oxidative stress and inflammasome activation. These processes are responsible for NASH development, resulting in hepatocellular injury, inflammation and fibrosis.

Figure 2

Mechanism of NAFLD pathogenesis in in vivo models. FA accumulation has a key role in NAFLD and NASH development. In ob/ob, Db/Db and Zucker models, a leptin-related increase in appetite results in insulin resistance and FA accumulation. HFD and fructose-rich diets induce insulin resistance and, secondarily, liposysis; HFD also causes a higher FA intake. In SREBP-c1 genetic model, FA increase is caused by a higher level of lipogenesis. MCD diet inhibits VLDL synthesis and export, as well as a GSH deficiency, leading to oxidative stress. ↑ indicates an increase. HFD, high-fat diet; SREBP-1c, sterol regulatory element-binding protein 1c; MCD, methionine and choline deficient; VLDL, very low-density lipoprotein.