Evolving concepts in the pathogenesis of NASH: beyond steatosis and inflammation

Abstract

Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis and inflammation and, in some patients, progressive fibrosis leading to cirrhosis. An understanding of the pathogenesis of NASH is still evolving but current evidence suggests multiple metabolic factors critically disrupt homeostasis and induce an inflammatory cascade and ensuing fibrosis. The mechanisms underlying these changes and the complex inter-cellular interactions that mediate fibrogenesis are yet to be fully elucidated. Lipotoxicity, in the setting of excess free fatty acids, obesity, and insulin resistance, appears to be the central driver of cellular injury via oxidative stress. Hepatocyte apoptosis and/or senescence contribute to activation of the inflammasome via a variety of intra- and inter-cellular signalling mechanisms leading to fibrosis. Current evidence suggests that periportal components, including the ductular reaction and expansion of the hepatic progenitor cell compartment, may be involved and that the Th17 response may mediate disease progression. This review aims to provide an overview of the pathogenesis of NASH and summarises the evidence pertaining to key mechanisms implicated in the transition from steatosis and inflammation to fibrosis. Currently there are limited treatments for NASH although an increasing understanding of its pathogenesis will likely improve the development and use of interventions in the future.

Figure 1.

The lipotoxicity model of pathogenesis in non-alcoholic steatohepatitis (NASH). In the setting of established insulin resistance (IR) and a diet high in saturated fats, hepatic traffic of excess free fatty acids (FFA) induces hepatocyte injury via lipotoxicity, caused by oxidative stress through the generation of lipotoxic metabolites (such as ceramides, diacylglycerols, and lysophosphatidyl choline) and reactive oxygen species (ROS). Protective mechanisms are shown as green arrows and injurious mechanisms are shown as red arrows. In the current model, the accumulation of triglyceride within hepatocytes likely represents a protective adaptation to excess FFA traffic, with only a minor contribution to the toxic effects of FFA flux via autophagy. (In the previous model of pathogenesis, the accumulation of hepatocyte triglyceride (“steatosis”) was considered a pre-requisite for oxidative stress, whereas emerging data suggest that steatosis occurs in parallel with lipotoxicity). A diet high in carbohydrates (CHO) and saturated fatty acids (SFAs) contributes to the production of excess FFA, as does the development of insulin resistance. In the chronic disease state, safe disposal of FFA via beta-oxidation and cellular antioxidant systems is overwhelmed resulting in the accumulation of excess ROS and subsequent oxidative stress, which results in NASH (Adapted from Hepatology 2010, 52, 774–788) [19].

Figure 2.

A schematic conceptualising the pathogenesis of NASH. Hepatocytes (H) are affected by lifestyle factors (a diet high in saturated fatty acids (SFA), obesity) and genetic predispositions contributing to the development of insulin resistance (IR) and hepatic steatosis (S). In some patients, these multiple parallel metabolic hits lead to cellular damage, via a process called “lipotoxicity”, involving excessive oxidative stress principally driven by the lipotoxic metabolites of SFA. Injured hepatocytes release DAMPs that initiate an inflammatory response, predominantly via toll-like receptors (TLRs), and activate pro-inflammatory signalling pathways in the setting of increased adipokine levels. Although injured hepatocytes undergo necrosis, apoptosis and senescence are alternative cell fates that are likely to be of greater importance to disease progression. Direct recruitment of Kupffer cells (KC) and other components of the innate immune response occurs with activation of the inflammasome and the coordinated release of pro-inflammatory and pro-fibrogenic cytokines and ligands (e.g., Hedgehog; Hh, and osteopontin; OPN). Hepatic stellate cells (HSC) are subsequently activated to produce extra-cellular matrix leading to progressive fibrosis, cirrhosis and its complications (e.g., hepatocellular carcinoma; HCC). Engulfment of apoptotic bodies and factors produced by senescent cells (upon adopting a “senescence-associated secretory phenotype; SASP”) can also influence HSC activity directly. The activity of KC promotes a pro-inflammatory microenvironment that initiates an adaptive immune response, likely representing a Th17 response. The appearance of a chronic portal inflammatory infiltrate accompanies a ductular reaction (DR) and hepatic progenitor cell (HPC) expansion. These factors are associated with progressive fibrosis that likely represents an imbalance of tissue damage and repair due to the influence of different inflammatory cells.