The effect of obeticholic acid on hepatic blood flow in isolated, perfused porcine liver: Correction of oxygen‐nutrient mismatch might be a putative mechanism of action in NASH

Abstract

AbstractBackgroundThe liver has a unique dual blood supply. Chronic excess nutrient delivery via the portal vein (PV), unmatched by hepatic artery (HA) oxygen could account for liver damage in NASH. Obeticholic acid (OCA), is a Farnesoid‐X‐receptor agonist with vascular targets in the liver. It has shown efficacy in NASH treatment. We hypothesized that increased oxygen delivery via HA vasodilatation, coupled with a reflex reduction in PV and nutrient flow due to the HA buffer response (HABR), could account for the therapeutic benefit in NASH.AimWe studied the direct effects of OCA on HA, PV and hepatic vein (HV) blood flow in an isolated, pump perfused porcine liver model.MethodsSix porcine livers (two controls) were perfused ex vivo with phosphate buffered saline (PBS), using a unique cardio‐emulation pump for the HA. OCA in solution with methyl cellulose, 0 mg/kg liver weight, followed by 0.14, 0.28, 0.56 and 1.12 mg/kg, was injected at 30‐min intervals, directly into the PV. Controls were perfused with PBS only.ResultsHA blood pressure, perfusate pH, perfusate dissolved oxygen (DO) and temperature remained relatively constant throughout. HA flow increased dose‐responsively up to 9.9 ± 8.9 per cent. Conversely, PV flow fell, up to −19 ± 16 per cent. HV flow rose and stabilized at 11 ± 11.8 per cent after the first dose. Control livers (n = 2) showed minor changes only.ConclusionOCA directly increased HA inflow, simultaneously decreasing PV flow, consistent with the hepatic artery buffer response, HABR. Increased oxygenation via the HA coupled with a reduction in nutrients via PV provides a rational concept for the etiology of NASH and the therapeutic benefit of OCA.