DDW ePoster Library

OXYGEN-NUTRIENT MISMATCH: A NOVEL CONCEPT TO EXPLAIN THE MECHANISM OF ACTION OF OBETICHOLIC ACID IN NASH
DDW ePoster Library. Lake-Bakaar G. 05/24/22; 355487; Tu1323
Dr. Gerond Lake-Bakaar
Dr. Gerond Lake-Bakaar
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Number: Tu1323
OXYGEN-NUTRIENT MISMATCH: A NOVEL CONCEPT TO EXPLAIN THE MECHANISM OF ACTION OF OBETICHOLIC ACID IN NASH

Society: AASLD
Track: Liver Diseases and Transplantation

Author(s): Gerond Lake-Bakaar1, 2, John Robertson3, Charles H. Aardema4

Institution(s): 1. Transplant, Porter Adventist Hospital, Golden, CO, United States. 2. Presbyterian/St. Luke's Medical Center, Denver, CO, United States. 3. Virginia Polytechnic Institute and State University, Blacksburg, VA, United States. 4. Biomedinnovations LLC, Denver, NC, United States.


Background and Aims: The oxygen-nutrient mismatch concept, first proposed for alcoholic steatohepatitis, ASH, equally applies to non-alcoholic steatohepatitis, NASH. Both are consequences of the unique dual liver blood supply. The hepatic artery, HA, provides over 50 percent of oxygen requirements and has myogenic elements for autoregulation. By contrast, the portal vein, PV, is rich in nutrients, but lacks autoregulatory capacity. Thus, under conditions of chronic alcohol or nutrient excess, oxygen-nutrient mismatch can occur. Furthermore, chronic obstructive sleep apnea (OSA), which is common in NASH, likely exacerbates the relative tissue hypoxia.

Obeticholic acid (OCA), is a highly selective, potent agonist for the Farnesoid-X-receptor (FXR). It is effective in the treatment of NASH fibrosis. Although anti-fibrotic, anti-inflammatory, and vascular targets have been identified, the mechanism of action is unclear.
We studied the effects of OCA on HA, PV, and hepatic vein, HV, flow in porcine liver perfused ex vivo with a cardio-emulation pump, the CaVESWave® system to determine whether vascular effects could explain its efficacy in the treatment of NASH.

Method: Six fresh porcine livers were continuously perfused with phosphate buffered saline (PBS). OCA dosing was delivered in solution with methyl cellulose as carrier, directly into the portal vein catheter. Perfusion was initiated with the HA settings at 120/80 mmHg, PV around 15 mmHg and temperature at 15° C. Flow rates in HA, PV and HV were measured continuously throughout. Carrier only was injected at 30 min intervals in the controls. For the treatment group, 0 mg OCA/kg liver weight, followed by 0.14, 0.28, 0.56 and 1.12 mg/kg, were injected at 30 min intervals.

Results: The cardio-emulated waveforms showed little variability, either before or after drug treatment (Fig. 1). HA pressure varied between 117-122 mmHg (systolic) and 75-84 mmHg (diastolic); perfusate pH between 7.35 and 7.4; and temperature 15.8 -17.5° C.
Control livers (n=2) showed minor changes in flow after treatments with vehicle (Fig. 2). The maximum percentage increase in HA flow was 3.3 + 3.5 and HV flow, 4.8 + 2.8. By contrast, PV flow was reduced by up to -9.1 + 5.9.
In OCA treated livers (n=4), there was a clear dose-response relationship between OCA and HA, HV and PV. Hepatic venous outflow and HA flow increased progressively to 11 + 11.8 and 9.9 + 8.9, respectively. Conversely, PV flow was reduced by up to -19 + 16%.

Conclusion: OCA in dose responsive manner increased HV and HA flow rates. It inversely reduced PV flow, consistent with an active hepatic artery buffering response. Thus, increased delivery of oxygen rich HA blood, coupled with reduced nutrient rich PV blood, provides a rational explanation for the beneficial effect OCA in NASH and suggests new therapeutic targets.
Number: Tu1323
OXYGEN-NUTRIENT MISMATCH: A NOVEL CONCEPT TO EXPLAIN THE MECHANISM OF ACTION OF OBETICHOLIC ACID IN NASH

Society: AASLD
Track: Liver Diseases and Transplantation

Author(s): Gerond Lake-Bakaar1, 2, John Robertson3, Charles H. Aardema4

Institution(s): 1. Transplant, Porter Adventist Hospital, Golden, CO, United States. 2. Presbyterian/St. Luke's Medical Center, Denver, CO, United States. 3. Virginia Polytechnic Institute and State University, Blacksburg, VA, United States. 4. Biomedinnovations LLC, Denver, NC, United States.


Background and Aims: The oxygen-nutrient mismatch concept, first proposed for alcoholic steatohepatitis, ASH, equally applies to non-alcoholic steatohepatitis, NASH. Both are consequences of the unique dual liver blood supply. The hepatic artery, HA, provides over 50 percent of oxygen requirements and has myogenic elements for autoregulation. By contrast, the portal vein, PV, is rich in nutrients, but lacks autoregulatory capacity. Thus, under conditions of chronic alcohol or nutrient excess, oxygen-nutrient mismatch can occur. Furthermore, chronic obstructive sleep apnea (OSA), which is common in NASH, likely exacerbates the relative tissue hypoxia.

Obeticholic acid (OCA), is a highly selective, potent agonist for the Farnesoid-X-receptor (FXR). It is effective in the treatment of NASH fibrosis. Although anti-fibrotic, anti-inflammatory, and vascular targets have been identified, the mechanism of action is unclear.
We studied the effects of OCA on HA, PV, and hepatic vein, HV, flow in porcine liver perfused ex vivo with a cardio-emulation pump, the CaVESWave® system to determine whether vascular effects could explain its efficacy in the treatment of NASH.

Method: Six fresh porcine livers were continuously perfused with phosphate buffered saline (PBS). OCA dosing was delivered in solution with methyl cellulose as carrier, directly into the portal vein catheter. Perfusion was initiated with the HA settings at 120/80 mmHg, PV around 15 mmHg and temperature at 15° C. Flow rates in HA, PV and HV were measured continuously throughout. Carrier only was injected at 30 min intervals in the controls. For the treatment group, 0 mg OCA/kg liver weight, followed by 0.14, 0.28, 0.56 and 1.12 mg/kg, were injected at 30 min intervals.

Results: The cardio-emulated waveforms showed little variability, either before or after drug treatment (Fig. 1). HA pressure varied between 117-122 mmHg (systolic) and 75-84 mmHg (diastolic); perfusate pH between 7.35 and 7.4; and temperature 15.8 -17.5° C.
Control livers (n=2) showed minor changes in flow after treatments with vehicle (Fig. 2). The maximum percentage increase in HA flow was 3.3 + 3.5 and HV flow, 4.8 + 2.8. By contrast, PV flow was reduced by up to -9.1 + 5.9.
In OCA treated livers (n=4), there was a clear dose-response relationship between OCA and HA, HV and PV. Hepatic venous outflow and HA flow increased progressively to 11 + 11.8 and 9.9 + 8.9, respectively. Conversely, PV flow was reduced by up to -19 + 16%.

Conclusion: OCA in dose responsive manner increased HV and HA flow rates. It inversely reduced PV flow, consistent with an active hepatic artery buffering response. Thus, increased delivery of oxygen rich HA blood, coupled with reduced nutrient rich PV blood, provides a rational explanation for the beneficial effect OCA in NASH and suggests new therapeutic targets.

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