To facilitate the development of novel diagnostic and
To facilitate the development of novel diagnostic and therapeutic interventions in NASH, a plethora of animal models have been used to identify molecular targets that are involved in the onset and progression of NASH. In view of recent advances in the understanding of the pathogenesis of NASH and progress in the clinical development of anti-NASH compounds, here we discuss the advantages and limitations of current in vivo mouse models of NASH.
NASH pathogenesis Current NAFLD treatment focuses on reducing metabolic risk factors, with lifestyle intervention being the mainstay therapy; however, this approach is often inefficient because of long periods of dieting and weight cycling . Recently, several breakthroughs have been made in the understanding of NASH pathogenesis, which is now known to be multifactorial, implicating several pathways in disease onset and progression. The pathogenesis of NASH was originally interpreted with a ‘dual-hit’ hypothesis, where steatosis (‘first hit’), resulting from increased lipolysis and lipogenesis (accentuated by insulin resistance), predisposes to the initiation of NASH through downstream (‘second hit’) proinflammatory mediators . Today, more complex ‘multiple-hit’ hypotheses have been proposed with the aim to explain how fatty acids and their metabolites promote NASH through multiple sequential or parallel cytotoxic pathways. In general, most recent hypotheses involve fatty acid-mediated lipotoxicity, which exhausts hepatocyte adaptive and regenerative responses, enabling accumulating oxidative stress to trigger hepatocyte necroinflammation, scar tissue formation (fibrosis), and disruption of hepatic cytoarchitecture, which can ultimately progress to cirrhosis and HCC 10, 11. A recent meta-analysis study of microarray data sets from rodent activated hepatic stellate nk1 receptor (HSCs, principal collagen-producing cells) underlined the complexity in fibrogenesis signaling pathways and suggested several novel candidate genes potentially serving as biomarkers or therapeutic targets for fibrotic NASH . NASH-specific pathways and druggable targets are also likely to be expanded in detail by ‘omics’ approaches (gut metagenomics, plasma metabolomics, and liver transcriptomics), which are increasingly applied in NASH research 13, 14, 15. There is evidence for concurrent immune imbalances in NASH. Although the immune signaling pathways involved are incompletely understood, activation of hepatic resident Kupffer cells (specialized macrophages) and neutrophils, in addition to the recruitment of other innate immune cells, is an important effector of parenchymal inflammation in NASH . Recent research on the potential role of the adaptive immune system in NASH has focused on proinflammatory T cells, including T helper (Th)-17 cells, which are the primary producers of the IL-17 family of proinflammatory cytokines . Given that IL-17 receptors are ubiquitously expressed in the liver (including by hepatocytes, Kupffer cells, and HSCs), dysregulated IL-17 secretion could lead to the mobilization of several deleterious cell signaling pathways 18, 19. These cell types also express other receptor families that have been implicated in NASH immunopathology, including Toll-like receptors (TLRs ) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs ). NLRs have received special attention because they are recognized as inflammasome sensory molecules. Metabolic inflammation triggered by the inflammasome (multiprotein complexes that assemble upon the sensing of danger signals and initiate the release of potent proinflammatory cytokines and chemokines) is suggested to link the metabolic syndrome and NAFLD , and could have an important role in the transition to fibrotic NASH . Gut microbial imbalances, bacterial translocation, and maladaptive host responses (‘gut dysbiosis’) are emerging as important contributing factors in the pathogenesis of obesity-related disorders, including NASH. The gut microbiota also has a critical role in bile acid metabolism, and might thereby indirectly modulate farnesoid X receptor (FXR) function, which is an important therapeutic target for NASH (see below). Gut dysbiosis causes gut dysmotility and inflammation. Importantly, dysbiosis can also lead to increased gut permeability to dietary factors and bacterial immunogens, thereby increasing hepatic exposure to injurious stimuli that promote hepatic inflammation and fibrogenesis. Compositional changes in the gut microbiome, reduced intestinal barrier function, translocated bacterial proinflammatory products, and associated inflammasome activation have been reported in NAFLD, and multiple studies in mouse models of NASH have supported these findings . However, most of the current evidence in this field comes from animal experiments, and further human studies are needed to determine whether gut dysbiosis translate into NASH pathology, and whether gut microbiome alterations precede and precipitate NASH, or simply reflect secondary adaptive responses to the dysmetabolic features of the disease.