| First Author | Brown ZJ | Year | 2018 |
| Journal | Cell Death Dis | Volume | 9 |
| Issue | 6 | Pages | 620 |
| PubMed ID | 29795111 | Mgi Jnum | J:318884 |
| Mgi Id | MGI:6863507 | Doi | 10.1038/s41419-018-0687-6 |
| Citation | Brown ZJ, et al. (2018) Carnitine palmitoyltransferase gene upregulation by linoleic acid induces CD4(+) T cell apoptosis promoting HCC development. Cell Death Dis 9(6):620 |
| abstractText | Hepatocellular carcinoma (HCC) is a common cause of cancer-related death worldwide. As obesity and diabetes become more prevalent, the contribution of non-alcoholic fatty liver disease (NAFLD) to HCC is rising. Recently, we reported intrahepatic CD4(+) T cells are critical for anti-tumor surveillance in NAFLD. Lipid accumulation in the liver is the hallmark of NAFLD, which may perturb T cell function. We sought to investigate how the lipid-rich liver environment influences CD4(+) T cells by focusing on carnitine palmitoyltransferase (CPT) family members, which control the mitochondrial beta-oxidation of fatty acids and act as key molecules in lipid catabolism. Linoleic acid (C18:2) co-localized within the mitochondria along with a corresponding increase in CPT gene upregulation. This CPT upregulation can be recapitulated by feeding mice with a high-C18:2 diet or the NAFLD promoting methionine-choline-deficient (MCD) diet. Using an agonist and antagonist, the induction of CPT genes was found to be mediated by peroxisome proliferator-activated receptor alpha (PPAR-alpha). CPT gene upregulation increased mitochondrial reactive oxygen species (ROS) and led to cell apoptosis. In vivo, using liver-specific inducible MYC transgenic mice fed MCD diet, blocking CPT with the pharmacological inhibitor perhexiline decreased apoptosis of intrahepatic CD4(+) T cells and inhibited HCC tumor formation. These results provide useful information for potentially targeting the CPT family to rescue intrahepatic CD4(+) T cells and to aid immunotherapy for NAFLD-promoted HCC. |
