Abstract / Summary
We profiled the hepatic transcriptome, lipidome and metabolome and serum metabolome in 211 MAFALDA participants with severe obesity undergoing bariatric surgery with liver biopsy. In 187 participants with paired samples, liver and serum levels of 40 matched metabolites correlated weakly (median {rho} 0.02), and steatosis and lobular inflammation were associated with 116 and 216 of 701 he-patic but [≤]1 of 653 serum metabolites. Hepatic amino acids were lower with lobular inflammation without serum changes, independently of tissue fat, dilution and glycemia, but largely shared with stea-tosis. Serum added little to clinical discrimination of steatosis (area under the curve 0.73 to 0.75) and nothing for inflammation, steatohepatitis or fibrosis. A polygenic score for hepatic lipid retention was associated with higher hepatic but lower serum triglycerides; its effects on inflammation and steatohepa-titis were largely mediated by liver fat. Circulating metabolites should be validated against histology, not interpreted as direct measures of hepatic metabolism.