Elevated S-Adenosylhomocysteine Induces Adipocyte Dysfunction to Promote Alcohol-Associated Liver Steatosis

Authors

Madan Kumar Arumugam, University of Nebraska Medical CenterFollow
Srinivas Chava, University of Nebraska Medical CenterFollow
Karuna Rasineni, University of Nebraska Medical CenterFollow
Matthew C. Paal, University of Nebraska Medical CenterFollow
Terrence Donohue, University of Nebraska Medical CenterFollow
Natalia A. Osna, University of Nebraska Medical CenterFollow
Kusum K. Kharbanda, University of Nebraska Medical CenterFollow

Document Type

Article

Journal Title

Scientific Reports

Publication Date

7-19-2021

Volume

11

Abstract

It has been previously shown that chronic ethanol administration-induced increase in adipose tissue lipolysis and reduction in the secretion of protective adipokines collectively contribute to alcohol-associated liver disease (ALD) pathogenesis. Further studies have revealed that increased adipose S-adenosylhomocysteine (SAH) levels generate methylation defects that promote lipolysis. Here, we hypothesized that increased intracellular SAH alone causes additional related pathological changes in adipose tissue as seen with alcohol administration. To test this, we used 3-deazaadenosine (DZA), which selectively elevates intracellular SAH levels by blocking its hydrolysis. Fully differentiated 3T3-L1 adipocytes were treated in vitro for 48 h with DZA and analysed for lipolysis, adipokine release and differentiation status. DZA treatment enhanced adipocyte lipolysis, as judged by lower levels of intracellular triglycerides, reduced lipid droplet sizes and higher levels of glycerol and free fatty acids released into the culture medium. These findings coincided with activation of both adipose triglyceride lipase and hormone sensitive lipase. DZA treatment also significantly reduced adipocyte differentiation factors, impaired adiponectin and leptin secretion but increased release of pro-inflammatory cytokines, IL-6, TNF and MCP-1. Together, our results demonstrate that elevation of intracellular SAH alone by DZA treatment of 3T3-L1 adipocytes induces lipolysis and dysregulates adipokine secretion. Selective elevation of intracellular SAH by DZA treatment mimics ethanol's effects and induces adipose dysfunction. We conclude that alcohol-induced elevations in adipose SAH levels contribute to the pathogenesis and progression of ALD.

DOI Link

10.1038/s41598-021-94180-x

ISSN

2045-2322

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Arumugam, Madan Kumar; Chava, Srinivas; Rasineni, Karuna; Paal, Matthew C.; Donohue, Terrence; Osna, Natalia A.; and Kharbanda, Kusum K., "Elevated S-Adenosylhomocysteine Induces Adipocyte Dysfunction to Promote Alcohol-Associated Liver Steatosis" (2021). Journal Articles: Internal Medicine. 20.
https://digitalcommons.unmc.edu/com_internal_articles/20