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. Issue 3 (21st July 2022)

• Record Type: Journal Article
• Authors: Lake‐Bakaar, Gerond; Robertson, John; Aardema, Charles
• Is Part Of: Clinical and translational discovery. Volume 2:Issue 3(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-07-21
• Subjects: cardio‐emulation pump -- hepatic artery blood flow -- liver -- oxygen‐nutrient mismatch -- porcine liver; Medicine -- Periodicals; Medicine; Periodicals; 616
• DOI: 10.1002/ctd2.98
• Languages: English
• ISSNs: 2768-0622

Abstract

Abstract: Background: The 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. Aim: We studied the direct effects of OCA on HA, PV and hepatic vein (HV) blood flow in an isolated, pump perfused porcine liver model. Methods: Six 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. Results: HA 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. Conclusion: OCA 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. Abstract : The unique dual liver blood supply.