Hydroxysteroid 17β-dehydrogenase 11 accumulation on lipid droplets promotes ethanol-induced cellular steatosis.

Autor:	Thomes PG; Department of Veterans' Affairs, VA-Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA. Electronic address: paul.thomes@unmc.edu., Strupp MS; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA., Donohue TM Jr; Department of Veterans' Affairs, VA-Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA., Kubik JL; Department of Veterans' Affairs, VA-Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA., Sweeney S; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA., Mahmud R; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA., Schott MB; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA., Schulze RJ; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA., McNiven MA; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA., Casey CA; Department of Veterans' Affairs, VA-Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2023 Apr; Vol. 299 (4), pp. 103071. Date of Electronic Publication: 2023 Feb 25.
DOI:	10.1016/j.jbc.2023.103071
Abstrakt:	Lipid droplets (LDs) are fat-storing organelles enclosed by a phospholipid monolayer, which harbors membrane-associated proteins that regulate distinct LD functions. LD proteins are degraded by the ubiquitin-proteasome system (UPS) and/or by lysosomes. Because chronic ethanol (EtOH) consumption diminishes the hepatic functions of the UPS and lysosomes, we hypothesized that continuous EtOH consumption slows the breakdown of lipogenic LD proteins targeted for degradation, thereby causing LD accumulation. Here, we report that LDs from livers of EtOH-fed rats exhibited higher levels of polyubiquitylated-proteins, linked at either lysine 48 (directed to proteasome) or lysine 63 (directed to lysosomes) than LDs from pair-fed control rats. MS proteomics of LD proteins, immunoprecipitated with UB remnant motif antibody (K-ε-GG), identified 75 potential UB proteins, of which 20 were altered by chronic EtOH administration. Among these, hydroxysteroid 17β-dehydrogenase 11 (HSD17β11) was prominent. Immunoblot analyses of LD fractions revealed that EtOH administration enriched HSD17β11 localization to LDs. When we overexpressed HSD17β11 in EtOH-metabolizing VA-13 cells, the steroid dehydrogenase 11 became principally localized to LDs, resulting in elevated cellular triglycerides (TGs). Ethanol exposure augmented cellular TG, while HSD17β11 siRNA decreased both control and EtOH-induced TG accumulation. Remarkably, HSD17β11 overexpression lowered the LD localization of adipose triglyceride lipase. EtOH exposure further reduced this localization. Reactivation of proteasome activity in VA-13 cells blocked the EtOH-induced rises in both HSD17β11 and TGs. Our findings indicate that EtOH exposure blocks HSD17β11 degradation by inhibiting the UPS, thereby stabilizing HSD17β11 on LD membranes, to prevent lipolysis by adipose triglyceride lipase and promote cellular LD accumulation. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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