Elevated S-adenosylhomocysteine induces adipocyte dysfunction to promote alcohol-associated liver steatosis

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...

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Autores principales:	Madan Kumar Arumugam, Srinivas Chava, Karuna Rasineni, Matthew C. Paal, Terrence M. Donohue, Natalia A. Osna, Kusum K. Kharbanda
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1360dbbed2824d8b8186be793004b477
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spelling	oai:doaj.org-article:1360dbbed2824d8b8186be793004b4772021-12-02T17:55:09ZElevated S-adenosylhomocysteine induces adipocyte dysfunction to promote alcohol-associated liver steatosis10.1038/s41598-021-94180-x2045-2322https://doaj.org/article/1360dbbed2824d8b8186be793004b4772021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94180-xhttps://doaj.org/toc/2045-2322Abstract 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.Madan Kumar ArumugamSrinivas ChavaKaruna RasineniMatthew C. PaalTerrence M. DonohueNatalia A. OsnaKusum K. KharbandaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Madan Kumar Arumugam Srinivas Chava Karuna Rasineni Matthew C. Paal Terrence M. Donohue Natalia A. Osna Kusum K. Kharbanda Elevated S-adenosylhomocysteine induces adipocyte dysfunction to promote alcohol-associated liver steatosis
description	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.
format	article
author	Madan Kumar Arumugam Srinivas Chava Karuna Rasineni Matthew C. Paal Terrence M. Donohue Natalia A. Osna Kusum K. Kharbanda
author_facet	Madan Kumar Arumugam Srinivas Chava Karuna Rasineni Matthew C. Paal Terrence M. Donohue Natalia A. Osna Kusum K. Kharbanda
author_sort	Madan Kumar Arumugam
title	Elevated S-adenosylhomocysteine induces adipocyte dysfunction to promote alcohol-associated liver steatosis
title_short	Elevated S-adenosylhomocysteine induces adipocyte dysfunction to promote alcohol-associated liver steatosis
title_full	Elevated S-adenosylhomocysteine induces adipocyte dysfunction to promote alcohol-associated liver steatosis
title_fullStr	Elevated S-adenosylhomocysteine induces adipocyte dysfunction to promote alcohol-associated liver steatosis
title_full_unstemmed	Elevated S-adenosylhomocysteine induces adipocyte dysfunction to promote alcohol-associated liver steatosis
title_sort	elevated s-adenosylhomocysteine induces adipocyte dysfunction to promote alcohol-associated liver steatosis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/1360dbbed2824d8b8186be793004b477
work_keys_str_mv	AT madankumararumugam elevatedsadenosylhomocysteineinducesadipocytedysfunctiontopromotealcoholassociatedliversteatosis AT srinivaschava elevatedsadenosylhomocysteineinducesadipocytedysfunctiontopromotealcoholassociatedliversteatosis AT karunarasineni elevatedsadenosylhomocysteineinducesadipocytedysfunctiontopromotealcoholassociatedliversteatosis AT matthewcpaal elevatedsadenosylhomocysteineinducesadipocytedysfunctiontopromotealcoholassociatedliversteatosis AT terrencemdonohue elevatedsadenosylhomocysteineinducesadipocytedysfunctiontopromotealcoholassociatedliversteatosis AT nataliaaosna elevatedsadenosylhomocysteineinducesadipocytedysfunctiontopromotealcoholassociatedliversteatosis AT kusumkkharbanda elevatedsadenosylhomocysteineinducesadipocytedysfunctiontopromotealcoholassociatedliversteatosis
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Elevated S-adenosylhomocysteine induces adipocyte dysfunction to promote alcohol-associated liver steatosis

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