Exogenous Liposomal Ceramide-C6 Ameliorates Lipidomic Profile, Energy Homeostasis, and Anti-Oxidant Systems in NASH
Zanieri, Francesca and Levi, Ana and Montefusco, David and Longato, Lisa and De Chiara, Francesco and Frenguelli, Luca and Omenetti, Sara and Andreola, Fausto and Luong, Tu Vinh and Massey, Veronica and Caballeria, Juan and Fondevila, Constantino and Shanmugavelandy, Sriram S and Fox, Todd and Mazza, Giuseppe and Argemi, Josepmaria and Bataller, Ramon and Cowart, Lauren Ashley and Kester, Mark and Pinzani, Massimo and Rombouts, Krista
(2020)
Exogenous Liposomal Ceramide-C6 Ameliorates Lipidomic Profile, Energy Homeostasis, and Anti-Oxidant Systems in NASH.
Cells, 9 (5).
p. 1237.
ISSN 2073-4409
Abstract
In non-alcoholic steatohepatitis (NASH), many lines of investigation have reported a dysregulation in lipid homeostasis, leading to intrahepatic lipid accumulation. Recently, the role of dysfunctional sphingolipid metabolism has also been proposed. Human and animal models of NASH have been associated with elevated levels of long chain ceramides and pro-apoptotic sphingolipid metabolites, implicated in regulating fatty acid oxidation and inflammation. Importantly, inhibition of de novo ceramide biosynthesis or knock-down of ceramide synthases reverse some of the pathology of NASH. In contrast, cell permeable, short chain ceramides have shown anti-inflammatory actions in multiple models of inflammatory disease. Here, we investigated non-apoptotic doses of a liposome containing short chain C6-Ceramide (Lip-C6) administered to human hepatic stellate cells (hHSC), a key effector of hepatic fibrogenesis, and an animal model characterized by inflammation and elevated liver fat content. On the basis of the results from unbiased liver transcriptomic studies from non-alcoholic fatty liver disease patients, we chose to focus on adenosine monophosphate activated kinase (AMPK) and nuclear factor-erythroid 2-related factor (Nrf2) signaling pathways, which showed an abnormal profile. Lip-C6 administration inhibited hHSC proliferation while improving anti-oxidant protection and energy homeostasis, as indicated by upregulation of Nrf2, activation of AMPK and an increase in ATP. To confirm these in vitro data, we investigated the effect of a single tail-vein injection of Lip-C6 in the methionine-choline deficient (MCD) diet mouse model. Lip-C6, but not control liposomes, upregulated phospho-AMPK, without inducing liver toxicity, apoptosis, or exacerbating inflammatory signaling pathways. Alluding to mechanism, mass spectrometry lipidomics showed that Lip-C6-treatment reversed the imbalance in hepatic phosphatidylcholines and diacylglycerides species induced by the MCD-fed diet. These results reveal that short-term Lip-C6 administration reverses energy/metabolic depletion and increases protective anti-oxidant signaling pathways, possibly by restoring homeostatic lipid function in a model of liver inflammation with fat accumulation.
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| Item Type: |
Article
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| Status: |
Published |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Zanieri, Francesca | | | | | Levi, Ana | | | | | Montefusco, David | | | | | Longato, Lisa | | | | | De Chiara, Francesco | | | | | Frenguelli, Luca | | | | | Omenetti, Sara | | | | | Andreola, Fausto | | | | | Luong, Tu Vinh | | | | | Massey, Veronica | | | | | Caballeria, Juan | | | | | Fondevila, Constantino | | | | | Shanmugavelandy, Sriram S | | | | | Fox, Todd | | | | | Mazza, Giuseppe | | | | | Argemi, Josepmaria | | | | | Bataller, Ramon | | | | | Cowart, Lauren Ashley | | | | | Kester, Mark | | | | | Pinzani, Massimo | | | | | Rombouts, Krista | | | |
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| Date: |
16 May 2020 |
| Date Type: |
Publication |
| Journal or Publication Title: |
Cells |
| Volume: |
9 |
| Number: |
5 |
| Publisher: |
MDPI AG |
| Page Range: |
p. 1237 |
| DOI or Unique Handle: |
10.3390/cells9051237 |
| Schools and Programs: |
School of Medicine > Medicine |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
non-alcoholic steatohepatitis (NASH), human hepatic stellate cells (hHSC), liposomes, ceramides, adenosine monophosphate-activated kinase (AMPK), nuclear factor-erythroid 2-related factor 2 (Nfe2l2/NRF2) |
| ISSN: |
2073-4409 |
| Official URL: |
http://dx.doi.org/10.3390/cells9051237 |
| Funders: |
Istituto Toscano Tumori, University of Florence, Regione Toscana “Ricerca Regionale in materia di salute D.D, Royal Free Charity, UCL NIHR Biomedical Research Centre, National Institute of Health, National Institute on Alcohol Abuse and Alcoholism, National Institute of Diabetes and Digestive and Kidney Diseases |
| Article Type: |
Research Article |
| Date Deposited: |
29 Jun 2021 18:37 |
| Last Modified: |
29 Jun 2021 18:37 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/41328 |
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