Cross-tissue omics analysis discovers coiled-coil domain containing 80 and superoxide dismutase 3 as novel serum biomarker candidates for non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a fast growing epidemic, which remains grossly underdiagnosed due to the lack of affordable and practical diagnostic tools in the primary health care setting. Here, we utilize dual-tissue RNA-seq data in subcutaneous adipose tissue and liver paired with liver histology-based NAFLD diagnosis from a cohort of obese individuals to discover serum biomarker candidates (SBCs) for obesity-related NAFLD. We hypothesize that in some obese individuals, obesity and its accompanying low-grade inflammation compromise the key functions of subcutaneous adipose tissue, preventing efficient adipogenesis and storage of fat into the subcutaneous fat depot, and thus driving ectopic fat accumulation into the liver. To identify subcutaneous adipose tissue-origin SBCs for the three primary NAFLD histology traits, steatosis, fibrosis, and non-alcoholic steatohepatitis (NASH), we scan for genes that are transcriptome-wide significantly differentially expressed (DE) for these NAFLD traits in subcutaneous adipose tissue but not in the liver, encode proteins secreted to serum, and show preferential expression in subcutaneous adipose tissue over the liver. Using a best subsets analysis, we identify the secreted adipokines CCDC80, SOD3, and COL6A2 as the key SBCs, the adipose expression of which explains the most significant amount of variance in steatosis, fibrosis, and NASH among the SBCs. We also show, by knockdown in human preadipocytes during adipogenesis, that the fibrosis and NASH SBCs, CCDC80 and SOD3, modulate the crucial adipogenesis genes, SREBF1 and LEP, emphasizing their premise as indicators for adipose-tissue origin, obesity-related NAFLD. Our results have a great translational potential to improve the diagnosis of obesity-related NAFLD by providing a blood panel of SBCs