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.