Leptin deficient rats develop nonalcoholic steatohepatitis with unique disease progression

Abstract

Nonalcoholic steatohepatitis (NASH) is an aggressive liver disease threatening public health, however its natural history is poorly understood. Unlike ob/ob mice, Lep^{∆I14/∆I14} rats develop unique NASH phenotype with steatosis, lymphocyte infiltration and ballooning after postnatal week 16. Using Lep^{∆I14/∆I14} rats as NASH model, we studied the natural history of NASH progression by performing an integrated analysis of hepatic transcriptome from postnatal week 4 to 48. Leptin deficiency results in a robust increase in expression of genes encoding 9 rate-limiting enzymes in lipid metabolism such as ACC and FASN. However, genes in positive regulation of inflammatory response are highly expressed at week 16 and then remain the steady elevated expression till week 48. The high expression of cytokines and chemokines including CCL2, TNFα, IL6 and IL1β is correlated with the phosphorylation of several key molecules in pathways such as JNK and NF-κB. Meanwhile, we observed cell infiltration of MPO⁺ neutrophils, CD8⁺ T cells, CD68⁺ hepatic macrophages and CCR2⁺ inflammatory monocyte-derived macrophages, together with macrophage polarization from M2 to M1. Importantly, Lep^{∆I14/∆I14} rats share more homologous genes with NASH patients than previously established mouse models and crab eating monkeys with spontaneous hepatic steatosis. Transcriptomic analysis showed that many drug targets in clinical trials can be evaluated in Lep^{∆I14/∆I14} rats.