Inter-tissue relationships of gene expression in liver, muscle and adipose tissue of children with end-stage chronic liver disease

Objectives End-stage chronic liver disease in children is associated with sarcopenia and aberrant adipose tissue mass. We investigated correlations between liver pathology-associated gene pathways (fibrosis, inflammation and steatosis) and metabolic genes in muscle and adipose tissue.Methods Liver, rectus abdominis muscle and subcutaneous adipose tissue were collected during liver transplant for microarray gene expression analysis. Patients underwent pre-transplant indirect calorimetry, anthropometry and laboratory assessments. Weighted gene co-expression network analysis identified highly correlated gene modules within each tissue and explored inter-tissue correlations.Results Nine patients were studied, three male:six female, age 7 months to 17 years. Liver gene clusters associated with fibrosis and ribosome function/protein secretion negatively correlated with muscle mitochondrial function genes and positively correlated with adipose tissue mitochondrial function genes. Notable correlations included a negative correlation between muscle growth hormone receptor (GHR) and liver ARID5B, MFGE8 and YWHAZ, and a positive correlation between adipose AKT1, ADG5, and SRM and liver RRAGA, YES1, EIF3M and COX3A. Liver inflammation-associated genes (vimentin, TIMP2, CXCL6 and endothelin-1) negatively correlated with adipose genes improving insulin sensitivity (THRSP) and fibrosis-related genes (KRT36, DMTN). Liver steatosis genes (ADRA2B) negatively correlated with adipose genes involved in adipogenesis (FGF10) and thyroid hormone metabolism (NHLH1).Conclusions Genes related to liver fibrosis and protein secretion negatively correlated with muscle and adipose tissue metabolism/proliferation genes. Liver inflammation and steatosis gene clusters were associated with muscle and adipose metabolism genes. This pilot study highlights important inter-tissue gene correlations warranting further investigation in paediatric end-stage chronic liver disease.