Nonalcoholic steatohepatitis (NASH) is an aggressive liver disease threatening human health, yet no medicine is developed to treat this disease. In this study, we first discovered that Leptin mutant rats (Lep^ΔI14/ΔI14) exhibit characteristic NASH phenotypes including steatosis, lymphocyte infiltration, and ballooning after postnatal week 16. We then examined NASH progression by performing an integrated analysis of hepatic transcriptome in Leptin-deficient rats from postnatal 4 to 48 weeks. Initially, simple steatosis in Lep^ΔI14/ΔI14 rats were observed with increased expression of the genes encoding for rate-limiting enzymes in lipid metabolism such as acetyl-CoA carboxylase and fatty acid synthase. When NASH phenotypes became well developed at postnatal week 16, we found gene expression changes in insulin resistance, inflammation, reactive oxygen species and endoplasmic reticulum stress. As NASH phenotypes further progressed with age, we observed elevated expression of cytokines and chemokines including C-C motif chemokine ligand 2, tumor necrosis factor ɑ, interleukin-6, and interleukin-1β together with activation of the c-Jun N-terminal kinase and nuclear factor-κB pathways. Histologically, livers in Lep^ΔI14/ΔI14 rats exhibited increased cell infiltration of MPO⁺ neutrophils, CD8⁺ T cells, CD68⁺ hepatic macrophages, and CCR2⁺ inflammatory monocyte-derived macrophages associated with macrophage polarization from M2 to M1. Subsequent cross-species comparison of transcriptomes in human, rat, and mouse NASH models indicated that Leptin-deficient rats bear more similarities to human NASH patients than previously established mouse NASH models. Taken together, our study suggests that Lep^ΔI14/ΔI14 rats are a valuable pre-clinical rodent model to evaluate NASH drug safety and efficacy.

非酒精性脂肪性肝炎 (NASH) 是一种威胁人类健康的侵袭性肝病，但尚未开发出治疗这种疾病的药物。在这项研究中，我们首先发现Leptin突变大鼠 ( Lep ^ΔI14/ΔI14 ) 在出生后 16 周后表现出特征性 NASH 表型，包括脂肪变性、淋巴细胞浸润和气球样变。然后我们通过对Leptin中的肝转录组进行综合分析来检查 NASH 进展-出生后 4 至 48 周的缺陷大鼠。最初，Lep ^{ΔI14/ΔI14中的简单脂肪变性}观察到大鼠在脂质代谢中编码限速酶的基因表达增加，例如乙酰辅酶A羧化酶和脂肪酸合酶。当 NASH 表型在出生后第 16 周发育良好时，我们发现胰岛素抵抗、炎症、活性氧和内质网应激的基因表达发生变化。随着 NASH 表型随着年龄的增长而进一步发展，我们观察到细胞因子和趋化因子的表达升高，包括 CC 基序趋化因子配体 2、肿瘤坏死因子 ɑ、白细胞介素 6 和白细胞介素 1β，以及 c-Jun N 末端激酶和核因子-κB途径。组织学上，Lep ^ΔI14/ΔI14大鼠的肝脏表现出 MPO ⁺中性粒细胞、CD8 ^{+细胞浸润增加}T 细胞、CD68 ⁺肝巨噬细胞和 CCR2 ⁺炎性单核细胞衍生的巨噬细胞与 M2 到 M1 的巨噬细胞极化相关。随后对人类、大鼠和小鼠 NASH 模型中转录组的跨物种比较表明，与先前建立的小鼠 NASH 模型相比，瘦素缺陷大鼠与人类 NASH 患者具有更多相似性。总之，我们的研究表明，Lep ^ΔI14/ΔI14大鼠是一种有价值的临床前啮齿动物模型，可用于评估 NASH 药物的安全性和有效性。