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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

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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
Status: Published
CreatorsEmailPitt UsernameORCID
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
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:
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


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