The molecular mechanisms behind human liver disease progression to cirrhosis remain elusive. Nuclear receptor small heterodimer partner (SHP/Nr0b2) is a critical regulator of liver function. SHP expression is diminished in human cirrhotic livers, suggesting a regulatory role in human liver diseases. We conducted the first comprehensive RNA sequencing analysis of SHP-/- mice, compared the results to human hepatitis C cirrhosis RNA-seq and non-alcoholic steatohepatitis (NASH) microarray datasets and verified novel results in human liver biospecimens. This approach revealed novel gene signatures associated with chronic liver disease and regulated by SHP. The physiological significance of markedly upregulated genes with minimally characterized functions in liver, such as peptidoglycan recognition protein 2 (PGLYRP2), dual specific phosphatase-4 (DUSP4), tetraspanin 4 (TSPAN4), thrombospondin 1 (THBS1), and SPARC-related modular calcium binding protein-2 (SMOC-2), was validated by q-PCR analysis of 126 human liver specimens including steatosis, fibrosis and NASH, alcohol and hepatitis C cirrhosis and in mouse models of liver inflammation and injury. This RNA-seq analysis identifies novel genes both regulated by the nuclear receptor SHP and implicated in the molecular pathogenesis of human chronic liver diseases. The results provide valuable information at the transcriptome level for characterizing mechanisms of these diseases.