Caspase-independent hepatocyte death: A result of the decrease of lysophosphatidylcholine acyltransferase 3 in non-alcoholic steatohepatitis.
1-Acylglycerophosphocholine O-Acyltransferase
/ genetics
Animals
Caspases
/ metabolism
Cell Death
Cell Line, Tumor
Diet, High-Fat
Dietary Sucrose
Disease Models, Animal
Down-Regulation
Hepatocytes
/ enzymology
Humans
Liver
/ enzymology
Lysophosphatidylcholines
/ metabolism
Male
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease
/ enzymology
Signal Transduction
ER stress
JNK
NAFLD
NASH
RIP1
lysophosphatidylcholine
palmitate
Journal
Journal of gastroenterology and hepatology
ISSN: 1440-1746
Titre abrégé: J Gastroenterol Hepatol
Pays: Australia
ID NLM: 8607909
Informations de publication
Date de publication:
Jul 2019
Jul 2019
Historique:
received:
04
06
2018
revised:
17
08
2018
accepted:
24
08
2018
pubmed:
31
8
2018
medline:
30
1
2020
entrez:
31
8
2018
Statut:
ppublish
Résumé
Lipotoxicity causes liver inflammation, which leads to non-alcoholic steatohepatitis (NASH). Lysophosphatidylcholine (LPC) is a causal agent of lipotoxicity. Recently, lysophosphatidylcholine acyltransferase (LPCAT) was identified as an enzyme that catalyzes the esterification of LPC, which potentially decreases LPC levels. However, the effect of LPCAT in lipotoxicity of the liver is not fully understood. Our aim was to determine whether LPCAT attenuates lipotoxicity in the liver. Mice fed a high-fat diet with sucrose (HFDS) or high-fat diet without sucrose, and Huh-7 cells treated with palmitate were used. Mice-fed HFDS showed advanced liver fibrosis as compared with mice-fed high-fat diet or normal chow. Lysophosphatidylcholine acyltransferase 3 (LPCAT3) mRNA expression in the liver was significantly decreased in the HFDS liver, and LPC content in the HFDS liver was significantly increased as compared with the other groups. When Huh-7 cells with short hairpin RNA-mediated knockdown of LPCAT3 (shLPCAT3 cells) were treated with palmitate, the intracellular LPC concentration and cell death were significantly higher than those in wild-type Huh-7 cells. Palmitate-induced cell death in shLPCAT3 was attenuated by a combination of receptor-interacting protein kinase 1 inhibitor with pan-caspase inhibitor. In contrast, intracellular LPC and palmitate-induced cell death were significantly lower in LPCAT3-overexpressing Huh-7 cells than in wild-type cells. Depletion of LPCAT3 in a mouse model of NASH leads to caspase-independent cell death, and LPCAT3 is a potential therapeutic target in NASH.
Sections du résumé
BACKGROUND AND AIMS
OBJECTIVE
Lipotoxicity causes liver inflammation, which leads to non-alcoholic steatohepatitis (NASH). Lysophosphatidylcholine (LPC) is a causal agent of lipotoxicity. Recently, lysophosphatidylcholine acyltransferase (LPCAT) was identified as an enzyme that catalyzes the esterification of LPC, which potentially decreases LPC levels. However, the effect of LPCAT in lipotoxicity of the liver is not fully understood. Our aim was to determine whether LPCAT attenuates lipotoxicity in the liver.
METHODS
METHODS
Mice fed a high-fat diet with sucrose (HFDS) or high-fat diet without sucrose, and Huh-7 cells treated with palmitate were used.
RESULTS
RESULTS
Mice-fed HFDS showed advanced liver fibrosis as compared with mice-fed high-fat diet or normal chow. Lysophosphatidylcholine acyltransferase 3 (LPCAT3) mRNA expression in the liver was significantly decreased in the HFDS liver, and LPC content in the HFDS liver was significantly increased as compared with the other groups. When Huh-7 cells with short hairpin RNA-mediated knockdown of LPCAT3 (shLPCAT3 cells) were treated with palmitate, the intracellular LPC concentration and cell death were significantly higher than those in wild-type Huh-7 cells. Palmitate-induced cell death in shLPCAT3 was attenuated by a combination of receptor-interacting protein kinase 1 inhibitor with pan-caspase inhibitor. In contrast, intracellular LPC and palmitate-induced cell death were significantly lower in LPCAT3-overexpressing Huh-7 cells than in wild-type cells.
CONCLUSION
CONCLUSIONS
Depletion of LPCAT3 in a mouse model of NASH leads to caspase-independent cell death, and LPCAT3 is a potential therapeutic target in NASH.
Substances chimiques
Dietary Sucrose
0
Lysophosphatidylcholines
0
1-Acylglycerophosphocholine O-Acyltransferase
EC 2.3.1.23
LPCAT3 protein, human
EC 2.3.1.23
LPCAT3 protein, mouse
EC 2.3.1.23
Caspases
EC 3.4.22.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1256-1262Subventions
Organisme : Daiichi Sankyo Co., Ltd.
Organisme : KAKENHI
ID : JP18K07980
Organisme : Grant-in-Aid for Scientific Research(C)
ID : JP18K07980
Informations de copyright
© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.