Obeticholic acid attenuates human immunodeficiency virus/alcohol metabolism-induced pro-fibrotic activation in liver cells

doi:10.4254/wjh.v12.i11.965

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World Journal of Hepatology

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1948-5182

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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Basic Study

World J Hepatol. Nov 27, 2020; 12(11): 965-975
Published online Nov 27, 2020. doi: 10.4254/wjh.v12.i11.965

Obeticholic acid attenuates human immunodeficiency virus/alcohol metabolism-induced pro-fibrotic activation in liver cells

Moses New-Aaron, Murali Ganesan, Raghubendra Singh Dagur, Kusum K Kharbanda, Larisa Y Poluektova, Natalia A Osna

Moses New-Aaron, Department of Environmental, Agriculture and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68105, United States

Moses New-Aaron, Murali Ganesan, Raghubendra Singh Dagur, Kusum K Kharbanda, Natalia A Osna, Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States

Murali Ganesan, Raghubendra Singh Dagur, Kusum K Kharbanda, Natalia A Osna, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, United States

Larisa Y Poluektova, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States

Author contributions: New-Aaron M and Dagur RS performed the experiments, acquired, analyzed and interpreted the data; New-Aaron M and Osna NA drafted the manuscript; Ganesan M, Kharbanda KK and Poluektova LY contributed to critical revision, editing of the manuscript; Osna NA contributed to conception, design and funding of the study; all authors approved the final version of the article.

Supported by The National Institutes of Health, No. R01AA027189-01A1.

Institutional review board statement: The study was reviewed and approved by the Subcommittee for Research and Development Review Board at Veterans Affairs Medical Center, Omaha, United States.

Conflict-of-interest statement: Moses New-Aaron, Murali Ganesan, Raghubendra Singh Dagur, Kusum K. Kharbanda, Larisa Y Poluektova , Natalia A. Osna. All authors have nothing to disclose.

Data sharing statement: No additional data are available.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Corresponding author: Natalia A Osna, MD, PhD, Associate Professor, Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, No. 4101 Woolworth Ave, Omaha, NE 68105, United States. nosna@unmc.edu

Received: July 16, 2020
Peer-review started: July 16, 2020
First decision: September 14, 2020
Revised: September 16, 2020
Accepted: October 5, 2020
Article in press: October 5, 2020
Published online: November 27, 2020
Processing time: 130 Days and 14.3 Hours

Core Tip

Core Tip: We investigated the ability of obeticholic acid (OCA) to reverse pro-fibrotic effects of human immunodeficiency virus (HIV) and ethanol metabolism in liver cells. Based on our previous studies, hepatocyte apoptosis occurs under combined exposure of cells to HIV and ethanol metabolites. The subsequent engulfment of HIV-containing apoptotic hepatocytes by hepatic stellate cells induced pro-fibrotic activation in these cells, thereby promoting fibrosis development. Here, we demonstrated that OCA attenuates hepatocyte apoptosis by preventing accumulation of HIV components in liver cells exposed to virus and acetaldehyde-generating system (AGS) mimicking natural ethanol metabolism in primary hepatocytes. These beneficial effects of OCA are attributed to suppression of oxidative stress leading to restoration of HIV-AGS-impaired proteasomal and lysosomal functions in liver cells. OCA also reduces activation of inflammasome in hepatic stellate cells and their pro-fibrotic activation. Thus, anti-fibrotic properties of OCA can be used for combined treatment of HIV-infected alcohol abusers with a high risk of liver fibrosis development.