Translational approaches: from fatty liver to non-alcoholic steatohepatitis

Abstract

Over the past few decades, non-alcoholic fatty liver disease (NAFLD) has become one, if not the most common, cause of chronic liver disease affecting both adults and children. The increasing number of cases at an early age is the most worrying aspect of this pathology, since it provides more time for its evolution. The spectrum of this disease ranges from liver steatosis to steatohepatitis, fibrosis and in some cases, hepatocellular carcinoma. NAFLD may not always be considered a benign disease and hepatologists must be cautious in the presence of fatty liver. This should prompt the use of the available experimental models to understand better the pathogenesis and to develop a rational treatment of a disease that is dangerously increasing. In spite of the growing efforts, the pathogenesis of NAFLD is still poorly understood. In the present article we review the most relevant hypotheses and evidence that account for the progression of NAFLD to non-alcoholic steatohepatitis (NASH) and fibrosis. The available in vitro and in vivo experimental models of NASH are discussed and revised in terms of their validity in translational studies. These studies must be aimed at the discovery of the still unknown triggers or mediators that induce the progression of hepatic inflammation, apoptosis and fibrosis.

Keywords: Experimental model; Fatty Liver; In vitro; Inflammation; Metabolic syndrome; Obesity.

Figure 1

Estimation of the main etiological incidence of past, present and future chronic liver diseases according to the available data from the United States[130] and Europe[131,132].

Figure 2

Extrahepatic factors involved in the pathogenesis of non-alcoholic fatty liver disease. The affected organs and their response are represented in a dynamic circle; in the center are indicated the main factors that contribute to the initiation/perpetuation of the hepatic injury (insulin resistance and chronic inflammatory state). The light blue arrows represent the organ-specific effects of each response. TNF-α: Tumor necrosis factor-α; MCP-1: Monocyte chemotactic protein 1; IL-6: Interleukin-6; FFA: Free fatty acids; LPS: Lipopolysaccharides; TLR: Toll-like receptor; GIP: Glucose-dependent insulinotropic peptide; GLP: Glucagon-like-peptide.

Figure 3

Effect of intracellular fat accumulation within the liver. Liver sensitization induces an alteration of the normal hepatic liver metabolism leading to simple steatosis with neutral triglyceride (TG) accumulation or in the more severe cases, to the production of intermediate products (DG and phospholipids) responsible for lipotoxicity. Alteration of several mediators of signaling pathways leads to the events observed during the progression from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) (hepatic insulin resistance, oxidative stress, inflammation, and fibrosis). IKKb: Protein Kinase-1-mediated IB Kinase; ROS: Reactive oxygen species; IL-6: Interleukin-6; TNFα: Tumor necrosis factor-α; IGF-1: Insulin-like growth factor-1; PDGF: Platelet-derivedgrowth factor; ECM: Extracellular matrix; MAPK: Mitogen-activated protein kinases; ERKs: Extracellular signal-regulated kinases; NF-κB: Nuclear factor κB.