Leptin deficiency leads to a unique natural history of NASH in rats

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 an inflection point of inflammation at postnatal week 16. Using Lep?I14/?I14 rats, we studied the natural history of NASH progression by performing an integrated analysis of hepatic transcriptome from postnatal week 4 to 48. Leptin deficiency leads to the precipitously increasing expression of genes encoding rate-limiting enzymes in lipid metabolism. However, hepatic inflammation related genes, pathways and immune-cell infiltration are restricted after week 16, implying an essential role of LEPTIN in regulating hepatic inflammation. Lep?I14/?I14 rats share more genes with NASH patients than known mouse models, therefore will provide a better genetic platform for studying NASH than mice. Overall design: We collected liver samples/biopsies from detailed 5 timepoints of both wild-type rats, leptin Knock-out rats and crab-eating monkeys and then conduct RNA-seq. Each sample contain 2~3 replicates.