Mouse Models of Nonalcoholic Steatohepatitis: Toward Optimization of Their Relevance to Human Nonalcoholic Steatohepatitis

Abstract

Nonalcoholic steatohepatitis (NASH) arises from a variable interplay between environmental factors and geneticdeterminants that cannot be completely replicated in animals. Notwithstanding, preclinical models are needed to understand NASH pathophysiology and test mechanism-based therapies. Among several mouse models of NASH, some exhibit the key pathophysiologic as well as histopathologic criteria for human NASH, whereas others may be useful to address specific questions. Models based on overnutrition with adipose restriction/inflammation and metabolic complications, particularly insulin resistance, may be most useful to investigate critical etiopathogenic factors. In-depth pathologic description is required for all models. Some models demonstrate hepatocyte ballooning, which can be confused with microvesicular steatosis, whereas demonstration of an inflammatory infiltrate and pattern of liver fibrosis compatible with human NASH is desirable in models used for pharmacologic testing. When mice with specific genetic strains or mutations that cause overeating consume a diet enriched with fat, modest amounts of cholesterol, and/ or simple sugars ("Western diet"), they readily develop obesity with liver disease similar to human NASH, including significant fibrosis. Purely dietary models, such as high-fat/high-cholesterol, Western diet, and choline-deficient, amino acid-defined, are similarly promising. We share concern about using models without weight gain, adipose pathology, or insulin resistance/hyperinsulinemia and with inadequate documentation of liver pathology. NASH-related fibrosis is a key endpoint in trials of possible therapies. When studied for this purpose, NASH models should be reproducible and show steatohepatitis (ideally with ballooning) and at least focal bridging fibrosis, while metabolic factors/disordered lipid partitioning should contribute to etiopathogenesis. Because murine models are increasingly used to explore pharmacologic therapies for NASH, we propose a minimum set of requirements that investigators, drug companies, and journals should consider to optimize their translational value. (Hepatology 2019;69:2241-2257).

RIP1 kinase activity promotes steatohepatitis through mediating cell death and inflammation in macrophages

“…In our study, we have established two entirely different murine models of steatohepatitis, both of which have been extensively used in NASH research but emphasizing different characteristics and mechanisms regarding steatohepatitis (31 (31,32). RIP1 kinase-dead (Rip1 K45A/K45A ) mice exhibited significantly attenuated liver injury, inflammation as well as fibrosis in both models, suggesting that the involvement of RIP1 kinase in NASH pathogenesis is not limited to specific model, but might generally apply to models induced by different factors or conditions.…”

β-arrestin: Dr Jekyll and Mr Hyde in NASH and fibrosis

“…more prominent fibrosis, such as the choline-deficient L-amino-defined diet could have been used. 2 Ex vivo, the authors confirmed ARRB1 expression in hepatocytes but not in Kupffer cells, suggesting that the increased macrophage infiltration found in Arrb1 knockout mice was secondary to hepatocyte damage. Moreover, overexpression of ARRB1 in human HepG2 cells and primary murine hepatocytes attenuated lipid accumulation after palmitate-supplementation, and decreased the expression of lipogenesis-associated genes, while downregulation of ARRB1 enhanced the expression of NFkB p65, promoting hepatocyte inflammatory pathways.…”

“…1 A central molecular driver of progression is lipotoxicity, a process involving multiple lipid species and pathways that result in hepatocyte damage, liver inflammation and fibrogenesis. 2 b-arrestin1 (ARRB1), 1 of the 2 b-arrestin isoforms, was initially described as a central regulator of G-protein-coupledreceptor signaling via receptor desensitization and internalization. [3][4][5] ARRB1 and ARRB2 are ubiquitously expressed as intracellular proteins.…”

“…[15][16][17] Another study in Gdf15-knockout and transgenic mice reported that GDF15 contributes to the improvement of liver fibrosis in the methioninecholine deficient (MCD) and the high fat/fructose/cholesterol (amylin) NASH models. 2,18 However, it is unclear whether this effect was due to weight loss or to direct anti-inflammatory and antifibrotic actions.…”

What influences treatment response in animal models of non-alcoholic fatty liver disease? A meta-analysis with meta-regression

“…Non-alcoholic fatty liver disease (NAFLD) is a highly active field of animal research [15,16] . NAFLD is a common condition characterised by increased liver fat (hepatic steatosis) that may progress to inflammation (non-alcoholic steatohepatitis (NASH)) and fibrosis [17] .…”