Obeticholic acid (OCA) has demonstrated significant beneficial effects in the treatment of non-alcoholic steatohepatitis, NASH. However, the associated mechanisms are not fully elucidated. Accumulating evidence continues to link hypoxia-regulated mechanisms and pathways with the pathogenesis of obesity and NASH. Specifically, oxygen therapy alleviates NASH. The hepatic artery HA delivers 50 percent of the oxygen requirements to the liver. OCA modulates intrahepatic vasodilator responses. Significant increase in HA blood flow associated with OCA treatment, offers alternative mechanisms of action for this drug in NASH. Using porcine livers, perfused ex vivo under constant pressure conditions with a cardio-emulation pump CaVESWave®, we studied the effect of progressively increasing doses of OCA on flow rates in the hepatic artery HA, portal vein PV and hepatic vein HV.
Following procurement and flushing, six livers (two controls) were placed in ice water baths, transported to the laboratory and connected to the CaVESWave® system. Total cold ischemic time was approximately 120 mins. Perfusion was initiated with the HA settings at 120/80 mmHg, PV below 15 mmHg and temperature at 15° C. Sensing data collected during perfusion, including pH, DO (dissolved oxygen), conductivity, temperature, pressure and flow rates on all vascular channels (hepatic artery, portal vein, hepatic vein) were collected. The treatment protocol commenced after the hepatic venous outflow stabilized beginning with an initial dose of 0.14 mg OCA/kg weight of liver and followed by increasing doses of 0.28, 0.56 and 1.12 mg/kg, added at 30 min intervals.
The control livers (n = 2) showed minor changes in flow after treatment with vehicle. The maximum increase in flow was 3.3 ± 3.5% for the HA and 4.8 ± 2.8% for the HV. By contrast, PV flow was reduced by up to −9.1 ± 5.9%. In the drug treated livers (n = 4), there was a clear dose relationship between OCA and HA, HV and PV flow rates. Hepatic venous outflow increased progressively to 11 ± 11.8% and HA to 9.9 ± 8.9%. Conversely, PV flow was reduced by −19 ± 16% (Figure 2).
In this non-cirrhotic porcine liver model, OCA in dose responsive manner increased flow rates in the HA, a major source of oxygenated blood to the liver. Increased hepatic oxygenation offers a possible mechanism of action of OCA in NASH. The concomitant reduction of PV flow could provide significant secondary benefits in the treatment of portal hypertension in cirrhotic livers.