Simultaneously targeting SOAT1 and CPT1A ameliorates hepatocellular carcinoma by disrupting lipid homeostasis.
Cell Death Discov
; 7(1): 125, 2021 May 29.
Article
en En
| MEDLINE
| ID: mdl-34052835
ABSTRACT
Lipid homeostasis plays a fundamental role in the development of hepatocellular carcinoma (HCC). However, the mechanisms that regulate lipid homeostasis to avoid lipotoxicity in HCC remain elusive. Here, we found high-fat diet (HFD) improved the expression of sterol o-acyltransferase1 (SOAT1) and carnitine palmitoyltransferase 1A (CPT1A) in diethylnitrosamine-induced HCC. Bioinformatic analysis showed that SOAT1-mediated fatty acid storage and CPT1A-mediated fatty acids oxidation (FAO) formed a double-negative feedback loop in HCC. We verified that SOAT1 inhibition enhanced CPT1A protein, which shuttled the released fatty acids into the mitochondria for oxidation in vivo and in vitro. Besides, we further confirmed that CPT1A inhibition converted excess fatty acids into lipid drops by SOAT1 in vitro. Simultaneously targeting SOAT1 and CPT1A by the small-molecule inhibitors avasimibe and etomoxir had synergistic anticancer efficacy in HCC in vitro and in vivo. Our study provides new mechanistic insights into the regulation of lipid homeostasis and suggests the combination of avasimibe and etomoxir is a novel strategy for HCC treatment.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Idioma:
En
Revista:
Cell Death Discov
Año:
2021
Tipo del documento:
Article
País de afiliación:
China