PMID- 35167910
OWN - NLM
STAT- MEDLINE
DCOM- 20220621
LR  - 20221004
IS  - 1600-0641 (Electronic)
IS  - 0168-8278 (Linking)
VI  - 77
IP  - 1
DP  - 2022 Jul
TI  - Inhibition of carnitine palmitoyltransferase 1A in hepatic stellate cells 
      protects against fibrosis.
PG  - 15-28
LID - S0168-8278(22)00077-0 [pii]
LID - 10.1016/j.jhep.2022.02.003 [doi]
AB  - BACKGROUND & AIMS: The pathogenesis of liver fibrosis requires activation of 
      hepatic stellate cells (HSCs); once activated, HSCs lose intracellular fatty 
      acids but the role of fatty acid oxidation and carnitine palmitoyltransferase 1A 
      (CPT1A) in this process remains largely unexplored. METHODS: CPT1A was found in 
      HSCs of patients with fibrosis. Pharmacological and genetic manipulation of CPT1A 
      were performed in human HSC cell lines and primary HCSs. Finally, we induced 
      fibrosis in mice lacking CPT1A specifically in HSCs. RESULTS: Herein, we show 
      that CPT1A expression is elevated in HSCs of patients with non-alcoholic 
      steatohepatitis, showing a positive correlation with the fibrosis score. This was 
      corroborated in rodents with fibrosis, as well as in primary human HSCs and LX-2 
      cells activated by transforming growth factor beta1 (TGFbeta1) and fetal bovine serum 
      (FBS). Furthermore, both pharmacological and genetic silencing of CPT1A prevent 
      TGFbeta1- and FBS-induced HSC activation by reducing mitochondrial activity. The 
      overexpression of CPT1A, induced by saturated fatty acids and reactive oxygen 
      species, triggers mitochondrial activity and the expression of fibrogenic 
      markers. Finally, mice lacking CPT1A specifically in HSCs are protected against 
      fibrosis induced by a choline-deficient high-fat diet, a methionine- and 
      choline-deficient diet, or treatment with carbon tetrachloride. CONCLUSIONS: 
      These results indicate that CPT1A plays a critical role in the activation of HSCs 
      and is implicated in the development of liver fibrosis, making it a potentially 
      actionable target for fibrosis treatment. LAY SUMMARY: We show that the enzyme 
      carnitine palmitoyltransferase 1A (CPT1A) is elevated in hepatic stellate cells 
      (HSCs) in patients with fibrosis and mouse models of fibrosis, and that CPT1A 
      induces the activation of these cells. Inhibition of CPT1A ameliorates fibrosis 
      by preventing the activation of HSCs.
CI  - Copyright (c) 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
FAU - Fondevila, Marcos F
AU  - Fondevila MF
AD  - Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto 
      de Investigacion Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatologia 
      de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain. 
      Electronic address: marcos.fernandez.fondevila@gmail.com.
FAU - Fernandez, Uxia
AU  - Fernandez U
AD  - Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto 
      de Investigacion Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatologia 
      de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain.
FAU - Heras, Violeta
AU  - Heras V
AD  - Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto 
      de Investigacion Sanitaria, Santiago de Compostela, Spain.
FAU - Parracho, Tamara
AU  - Parracho T
AD  - Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto 
      de Investigacion Sanitaria, Santiago de Compostela, Spain.
FAU - Gonzalez-Rellan, Maria J
AU  - Gonzalez-Rellan MJ
AD  - Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto 
      de Investigacion Sanitaria, Santiago de Compostela, Spain.
FAU - Novoa, Eva
AU  - Novoa E
AD  - Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto 
      de Investigacion Sanitaria, Santiago de Compostela, Spain.
FAU - Porteiro, Begona
AU  - Porteiro B
AD  - Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto 
      de Investigacion Sanitaria, Santiago de Compostela, Spain.
FAU - Alonso, Cristina
AU  - Alonso C
AD  - OWL Metabolomics, Technology Park of Bizkaia, Derio, Bizkaia, Spain.
FAU - Mayo, Rebeca
AU  - Mayo R
AD  - OWL Metabolomics, Technology Park of Bizkaia, Derio, Bizkaia, Spain.
FAU - da Silva Lima, Natalia
AU  - da Silva Lima N
AD  - Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto 
      de Investigacion Sanitaria, Santiago de Compostela, Spain.
FAU - Iglesias, Cristina
AU  - Iglesias C
AD  - Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto 
      de Investigacion Sanitaria, Santiago de Compostela, Spain.
FAU - Filliol, Aveline A
AU  - Filliol AA
AD  - Department of Medicine, Columbia University, New York, NY, USA.
FAU - Senra, Ana
AU  - Senra A
AD  - Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto 
      de Investigacion Sanitaria, Santiago de Compostela, Spain.
FAU - Delgado, Teresa C
AU  - Delgado TC
AD  - Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), 
      Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain; 
      CIBER Enfermedades Hepaticas y Digestivas (CIBERehd), Spain.
FAU - Woodhoo, Ashwin
AU  - Woodhoo A
AD  - Gene Regulatory Control in Disease, CIMUS, University of Santiago de Compostela, 
      Santiago de Compostela, Spain.
FAU - Herrero, Laura
AU  - Herrero L
AD  - CIBER Fisiopatologia de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud 
      Carlos III, Spain; Department of Biochemistry and Physiology, School of Pharmacy 
      and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), 
      Barcelona, Spain.
FAU - Serra, Dolors
AU  - Serra D
AD  - CIBER Fisiopatologia de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud 
      Carlos III, Spain; Department of Biochemistry and Physiology, School of Pharmacy 
      and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), 
      Barcelona, Spain.
FAU - Prevot, Vincent
AU  - Prevot V
AD  - Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the 
      Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S 1172, European 
      Genomic Institute for Diabetes (EGID), F-59000 Lille, France.
FAU - Schwaninger, Markus
AU  - Schwaninger M
AD  - University of Lubeck, Institute for Experimental and Clinical Pharmacology and 
      Toxicology, Lubeck, Germany.
FAU - Lopez, Miguel
AU  - Lopez M
AD  - Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto 
      de Investigacion Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatologia 
      de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain.
FAU - Dieguez, Carlos
AU  - Dieguez C
AD  - Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto 
      de Investigacion Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatologia 
      de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain.
FAU - Millet, Oscar
AU  - Millet O
AD  - OWL Metabolomics, Technology Park of Bizkaia, Derio, Bizkaia, Spain; Liver 
      Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque 
      Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain.
FAU - Mato, Jose M
AU  - Mato JM
AD  - OWL Metabolomics, Technology Park of Bizkaia, Derio, Bizkaia, Spain; Liver 
      Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque 
      Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain.
FAU - Cubero, Francisco J
AU  - Cubero FJ
AD  - Department of Immunology, Ophthalmology & ENT, Complutense University School of 
      Medicine, 28040 Madrid, Spain; Health Research Institute Gregorio Maranon 
      (IiSGM), 28007 Madrid, Spain.
FAU - Varela-Rey, Marta
AU  - Varela-Rey M
AD  - Gene Regulatory Control in Disease, CIMUS, University of Santiago de Compostela, 
      Santiago de Compostela, Spain.
FAU - Iruzubieta, Paula
AU  - Iruzubieta P
AD  - Gastroenterology and Hepatology Department, Marques de Valdecilla University 
      Hospital. Clinical and Translational Digestive Research Group, IDIVAL, Santander, 
      Spain.
FAU - Crespo, Javier
AU  - Crespo J
AD  - Gastroenterology and Hepatology Department, Marques de Valdecilla University 
      Hospital. Clinical and Translational Digestive Research Group, IDIVAL, Santander, 
      Spain.
FAU - Martinez-Chantar, Maria L
AU  - Martinez-Chantar ML
AD  - Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), 
      Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain; 
      CIBER Enfermedades Hepaticas y Digestivas (CIBERehd), Spain.
FAU - Schwabe, Robert F
AU  - Schwabe RF
AD  - Department of Medicine, Columbia University, New York, NY, USA.
FAU - Nogueiras, Ruben
AU  - Nogueiras R
AD  - Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto 
      de Investigacion Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatologia 
      de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain; 
      Galician Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, 
      Spain. Electronic address: ruben.nogueiras@usc.es.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220212
PL  - Netherlands
TA  - J Hepatol
JT  - Journal of hepatology
JID - 8503886
RN  - 0 (Fatty Acids)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
RN  - N91BDP6H0X (Choline)
SB  - IM
MH  - Animals
MH  - *Carnitine O-Palmitoyltransferase/genetics/metabolism
MH  - Choline
MH  - Fatty Acids/metabolism
MH  - Fibrosis
MH  - *Hepatic Stellate Cells/metabolism
MH  - Humans
MH  - Liver/pathology
MH  - Liver Cirrhosis/metabolism/prevention & control
MH  - Mice
OTO - NOTNLM
OT  - CPT1A
OT  - NASH
OT  - beta oxidation
OT  - fatty acids
OT  - fibrosis
OT  - metabolism
COIS- Conflict of interest The authors declare that they have no conflicts of interest 
      related to the study. Please refer to the accompanying ICMJE disclosure forms for 
      further details.
EDAT- 2022/02/16 06:00
MHDA- 2022/06/22 06:00
CRDT- 2022/02/15 20:12
PHST- 2021/09/27 00:00 [received]
PHST- 2022/02/02 00:00 [revised]
PHST- 2022/02/03 00:00 [accepted]
PHST- 2022/02/16 06:00 [pubmed]
PHST- 2022/06/22 06:00 [medline]
PHST- 2022/02/15 20:12 [entrez]
AID - S0168-8278(22)00077-0 [pii]
AID - 10.1016/j.jhep.2022.02.003 [doi]
PST - ppublish
SO  - J Hepatol. 2022 Jul;77(1):15-28. doi: 10.1016/j.jhep.2022.02.003. Epub 2022 Feb 
      12.