How Useful Are Monogenic Rodent Models for the Study of Human Non-Alcoholic Fatty Liver Disease?

Abstract

Improving understanding of the genetic basis of human non-alcoholic fatty liver disease (NAFLD) has the potential to facilitate risk stratification of affected patients, permit personalized treatment, and inform development of new therapeutic strategies. Animal models have been widely used to interrogate the pathophysiology of, and genetic predisposition to, NAFLD. Nevertheless, considerable interspecies differences in intermediary metabolism potentially limit the extent to which results can be extrapolated to humans. For example, human genome-wide association studies have identified polymorphisms in PNPLA3 and TM6SF2 as the two most prevalent determinants of susceptibility to NAFLD and its inflammatory component (NASH), but animal models of these mutations have had only variable success in recapitulating this link. In this review, we critically appraise selected murine monogenic models of NAFLD, NASH, and hepatocellular carcinoma (HCC) with a focus on how closely they mirror human disease.

Keywords: animal model; genetic models; metabolic syndrome; steatohepatitis; steatosis.

Figure 1

Factors implicated in hepatic steatosis. Pre-hepatic factors lead to increased substrate flux to the liver by both increased load (e.g., raised fatty acid delivery) and altered composition (e.g., increased fructose). Hyperphagia causes provision of excess macronutrients, which contributes to overload of white adipose tissue (via obesity). Lipodystrophy causes functional or anatomical failure of adipose, with the resulting spill over of substrates passing to the liver. Insulin resistance contributes to hormonal changes (e.g., raised insulin, low adiponectin) that alter intra-hepatic metabolism of lipids. Intestinal dysbiosis influences both substrate delivery to the liver and generation of gut-derived hormones (e.g., elevated GLP-1). Key: hormones are in blue, examples of genes involved in monogenic disorders are in green, and examples of genes with pro-steatotic common polymorphisms are in red.