Hepatic insulin resistance is the basis of bile acid dysmetabolism in metabolic dysfunction-associated steatotic liver disease

Bile acids (BAs) are liver-synthesized steroids that facilitate lipid digestion and regulate diverse metabolic pathways. Because of their cytotoxicity, excessive hepatic BA accumulation has been implicated in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). Although circulating BAs are frequently elevated in MASLD, it is unclear whether similar alterations occur within the liver. Moreover, the strong overlap between MASLD and metabolic syndrome complicates efforts to distinguish BA changes driven by liver disease from those arising due to broader metabolic dysfunction. Here we show in a series of human studies that the BA dysmetabolism in MASLD originates from insulin resistance rather than hepatic steatosis. We found that circulating BA concentrations are twofold higher in patients with MASLD than in healthy controls, despite similar intrahepatic levels. Causal inference using a MASLD genetic risk score indicated that this elevation is not attributable to hepatic steatosis. Instead, circulating BAs, but not intrahepatic BAs, associate with glycemia and hepatic insulin sensitivity. We found reduced expression of the BA uptake transporter NTCP in insulin-resistant individuals, implicating impaired hepatic BA clearance. During hepatic vein catheterization, insulin acutely lowered conjugated BA concentrations in hepatic venous blood, consistent with diminished splanchnic BA spillover. Physiology-based simulations of impaired hepatic BA clearance recapitulated the human phenotype. Taken together, our findings argue against a major role for BAs in MASLD pathogenesis but reveal a previously unrecognized link between circulating BA dynamics and hepatic insulin action.