Palmitate activation by fatty acid transport protein 4 as a model system for hepatocellular apoptosis and steatosis.
Biochim Biophys Acta
; 1851(5): 549-65, 2015 May.
Article
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| MEDLINE
| ID: mdl-25603556
ABSTRACT
Fatty acid transport protein (FATP) 4 is a minor FATP in the liver but it has some activity towards palmitate 160 (Pal). We here chose FATP4 as a representative model enzyme for acyl-CoA synthetases (ACSs), and FATPs to determine whether Pal activation would lead to apoptosis and alteration in lipid metabolism. By using FATP4 overexpressed (FATP4) Huh-7 cells, we showed that FATP4 was localized in the endoplasmic reticulum (ER) and mitochondria of FATP4 cells. FATP4 cells were more responsive to Pal than the control GFP cells in increasing palmitoyl-CoA and oleoyl-CoA activities as well as apoptosis by ~2-3 folds. The lipoapoptosis susceptibility by FATP4 was coupled with the increased JNK, PUMA, caspase3, PARP-1 activation as well as Rac-1-mediated cytoskeletal reorganization, and decreased insulin sensitivity. This was associated with increased contents of neutral lipids and significant alteration in composition of phospholipids and sphingolipids including increased lysophosphatidylcholine (LPC), ceramide, and hexosylceramide, as well as an increase of saturatedpolyunsaturated fatty acid ratio in LPC and PC, but a decrease of this ratio in phosphatidylethanolamine pool. By use of ceramide synthase inhibitors, our results showed that FATP4-sensitized lipoapoptosis was not mediated by ceramides. Moreover, FATP4 expression was increased in fatty livers in vivo. Thus, our model system has provided a clue that Pal activation FATP4 triggers hepatocellular apoptosis via altered phospholipid composition and steatosis by acylation into complex lipids. This may be a redundant mechanism for other ER-localizing ACSs and FATPs in the liver, and hence their involvement in the development of fatty liver disease.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Apoptosis
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Ácido Palmítico
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Hepatocitos
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Enfermedad del Hígado Graso no Alcohólico
Tipo de estudio:
Etiology_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Biochim Biophys Acta
Año:
2015
Tipo del documento:
Article
País de afiliación:
Alemania