PMID- 32429478
OWN - NLM
STAT- MEDLINE
DCOM- 20210224
LR  - 20211211
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 9
IP  - 5
DP  - 2020 May 16
TI  - Exogenous Liposomal Ceramide-C6 Ameliorates Lipidomic Profile, Energy 
      Homeostasis, and Anti-Oxidant Systems in NASH.
LID - 10.3390/cells9051237 [doi]
LID - 1237
AB  - 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.
FAU - Zanieri, Francesca
AU  - Zanieri F
AD  - Department of Experimental and Clinical Medicine and Center of Excellence 
      "DENOthe", University of Florence, 50134 Florence, Italy.
FAU - Levi, Ana
AU  - Levi A
AUID- ORCID: 0000-0003-1966-6614
AD  - Institute for Liver & Digestive Health, Royal Free, University College London 
      UCL, London NW3 2PF, UK.
FAU - Montefusco, David
AU  - Montefusco D
AD  - Virginia Commonwealth University, Richmond, VA 23219, USA.
FAU - Longato, Lisa
AU  - Longato L
AD  - Institute for Liver & Digestive Health, Royal Free, University College London 
      UCL, London NW3 2PF, UK.
FAU - De Chiara, Francesco
AU  - De Chiara F
AD  - Institute for Liver & Digestive Health, Royal Free, University College London 
      UCL, London NW3 2PF, UK.
FAU - Frenguelli, Luca
AU  - Frenguelli L
AD  - Institute for Liver & Digestive Health, Royal Free, University College London 
      UCL, London NW3 2PF, UK.
FAU - Omenetti, Sara
AU  - Omenetti S
AUID- ORCID: 0000-0002-2443-3631
AD  - Department of Experimental and Clinical Medicine and Center of Excellence 
      "DENOthe", University of Florence, 50134 Florence, Italy.
FAU - Andreola, Fausto
AU  - Andreola F
AUID- ORCID: 0000-0003-4926-0121
AD  - Institute for Liver & Digestive Health, Royal Free, University College London 
      UCL, London NW3 2PF, UK.
FAU - Luong, Tu Vinh
AU  - Luong TV
AUID- ORCID: 0000-0002-7598-7319
AD  - Institute for Liver & Digestive Health, Royal Free, University College London 
      UCL, London NW3 2PF, UK.
AD  - Department of Cellular Pathology, Royal Free Hospital, London NW3 2PF, UK.
FAU - Massey, Veronica
AU  - Massey V
AD  - Division of Hepatology and Gastroenterology, Departments of Medicine and 
      Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, 
      USA.
FAU - Caballeria, Juan
AU  - Caballeria J
AD  - Hepatology, Hospital Clinic, IDIBAPS, CIBERehd, 08036 Barcelona, Spain.
FAU - Fondevila, Constantino
AU  - Fondevila C
AD  - Liver Transplant Unit, Department of Surgery, Hospital Clinic, University of 
      Barcelona, 08036 Barcelona, Spain.
FAU - Shanmugavelandy, Sriram S
AU  - Shanmugavelandy SS
AD  - Department of Pharmacology, Penn State University College of Medicine, Hershey, 
      PA 17033, USA.
FAU - Fox, Todd
AU  - Fox T
AUID- ORCID: 0000-0001-5170-3951
AD  - Department of Pharmacology, Penn State University College of Medicine, Hershey, 
      PA 17033, USA.
FAU - Mazza, Giuseppe
AU  - Mazza G
AD  - Institute for Liver & Digestive Health, Royal Free, University College London 
      UCL, London NW3 2PF, UK.
FAU - Argemi, Josepmaria
AU  - Argemi J
AD  - Department of Medicine, Pittsburgh Liver Research Center, University of 
      Pittsburgh, Pittsburgh, PA 15261, USA.
FAU - Bataller, Ramon
AU  - Bataller R
AD  - Division of Hepatology and Gastroenterology, Departments of Medicine and 
      Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, 
      USA.
AD  - Department of Medicine, Pittsburgh Liver Research Center, University of 
      Pittsburgh, Pittsburgh, PA 15261, USA.
FAU - Cowart, Lauren Ashley
AU  - Cowart LA
AD  - Virginia Commonwealth University, Richmond, VA 23219, USA.
AD  - Hunter Holmes McGuire VA Medical Center, Richmond, VA 23219, USA.
FAU - Kester, Mark
AU  - Kester M
AD  - Department of Pharmacology, Penn State University College of Medicine, Hershey, 
      PA 17033, USA.
AD  - Department of Pharmacology, University of Virginia School of Medicine, P.O. Box 
      800735, Charlottesville, VA 22908, USA.
FAU - Pinzani, Massimo
AU  - Pinzani M
AD  - Department of Experimental and Clinical Medicine and Center of Excellence 
      "DENOthe", University of Florence, 50134 Florence, Italy.
AD  - Institute for Liver & Digestive Health, Royal Free, University College London 
      UCL, London NW3 2PF, UK.
AD  - Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London NW3 
      2PF, UK.
FAU - Rombouts, Krista
AU  - Rombouts K
AUID- ORCID: 0000-0001-9440-0571
AD  - Department of Experimental and Clinical Medicine and Center of Excellence 
      "DENOthe", University of Florence, 50134 Florence, Italy.
AD  - Institute for Liver & Digestive Health, Royal Free, University College London 
      UCL, London NW3 2PF, UK.
LA  - eng
GR  - P30 DK120531/DK/NIDDK NIH HHS/United States
GR  - U01 AA026264/AA/NIAAA NIH HHS/United States
GR  - U01 AA026972/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200516
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Antioxidants)
RN  - 0 (Ceramides)
RN  - 0 (Diglycerides)
RN  - 0 (Liposomes)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Phosphatidylcholines)
RN  - 0 (Protein Subunits)
RN  - 038753E78J (N-caproylsphingosine)
RN  - AE28F7PNPL (Methionine)
RN  - EC 2.7.4.3 (Adenylate Kinase)
RN  - N91BDP6H0X (Choline)
SB  - IM
MH  - Adenylate Kinase/metabolism
MH  - Animals
MH  - Antioxidants/*metabolism
MH  - Apoptosis/drug effects
MH  - Cell Proliferation/drug effects
MH  - Ceramides/*pharmacology
MH  - Choline
MH  - Diet
MH  - Diglycerides/metabolism
MH  - *Energy Metabolism/drug effects
MH  - Fatty Liver/complications/pathology
MH  - Feeding Behavior
MH  - Hematopoietic Stem Cells/metabolism
MH  - *Homeostasis/drug effects
MH  - Humans
MH  - *Lipidomics
MH  - Liposomes
MH  - Male
MH  - Methionine/deficiency
MH  - Mice, Inbred BALB C
MH  - NF-E2-Related Factor 2/genetics/metabolism
MH  - Non-alcoholic Fatty Liver Disease/complications/genetics/*metabolism/pathology
MH  - Phosphatidylcholines/metabolism
MH  - Phosphorylation/drug effects
MH  - Protein Subunits/metabolism
MH  - Signal Transduction/drug effects
PMC - PMC7290333
OTO - NOTNLM
OT  - adenosine monophosphate-activated kinase (AMPK)
OT  - apoptosis
OT  - ceramides
OT  - diacylglycerol (DG)
OT  - human hepatic stellate cells (hHSC)
OT  - inflammation
OT  - lipidomics
OT  - liposomes
OT  - methionine-choline deficient diet (MCD)
OT  - non-alcoholic steatohepatitis (NASH)
OT  - nuclear factor-erythroid 2-related factor 2 (Nfe2l2/NRF2)
OT  - phosphatidylcholine (PC)
COIS- "The funders had no role in the design of the study; in the collection, analyses, 
      or interpretation of data; in the writing of the manuscript; or in the decision 
      to publish the results". Penn State Research Foundation has licensed ceramide 
      nanotechnology to Keystone Nano, Inc. (PA, USA) and M.K. is cofounder and Chief 
      Medical Officer of Keystone Nano. R.B. has done consulting services for Verlyx 
      Pharma Inc. G.M., L.F., and L.L. are now full time employees at Engitix Ltd., and 
      G.M., L.L., M.P., and K.R. own shares in Engitix Ltd. M.P. and K.R. receive 
      consultancies from Engitix Ltd.
EDAT- 2020/05/21 06:00
MHDA- 2021/02/25 06:00
PMCR- 2020/05/01
CRDT- 2020/05/21 06:00
PHST- 2020/04/10 00:00 [received]
PHST- 2020/05/05 00:00 [revised]
PHST- 2020/05/13 00:00 [accepted]
PHST- 2020/05/21 06:00 [entrez]
PHST- 2020/05/21 06:00 [pubmed]
PHST- 2021/02/25 06:00 [medline]
PHST- 2020/05/01 00:00 [pmc-release]
AID - cells9051237 [pii]
AID - cells-09-01237 [pii]
AID - 10.3390/cells9051237 [doi]
PST - epublish
SO  - Cells. 2020 May 16;9(5):1237. doi: 10.3390/cells9051237.