Carnitine palmitoyltransferase gene upregulation by linoleic acid induces CD4+ T cell apoptosis promoting HCC development
Brown ZJ, Fu Q, Ma C, Kruhlak M, Zhang H, Luo J, Heinrich B, Yu SJ, Zhang Q, Wilson A, Shi ZD, Swenson R, Greten TF
Cell death & disease · 120 citations
How it was studied
- Design
- Animal study (classified by our AI screen)
- Studied in
- Animals
- Main outcome
- Clinical events such as disease or death
Who paid for it
- Funding
- Independent funding
- Government
- National Institutes of Health
- Government
- National Cancer Institute
Based on 2 listed funder(s) and full-text disclosure statement.
Publication
- Published
- 2018-05-23 · Cell Death Dis · vol. 9 · issue 6 · p. 620
- Publisher
- Springer Nature
- Cited
- 144 citations · more than 97% of similar papers · 6.1× the field average
- Impact
- Top 10% most cited in its field
- References
- 45 works
- Access
- Open access (journal) · CC-BY
- Research areas
- Liver Disease Diagnosis and Treatment · Peroxisome Proliferator-Activated Receptors · Cancer, Lipids, and Metabolism
- Keywords
- Downregulation and upregulation, Biology, Fatty liver, Beta oxidation, Endocrinology, Cancer research, Carnitine, Internal medicine, Apoptosis, Biochemistry, Medicine, Metabolism
- MeSH
- cd4-positive t-lymphocytes, 3t3 cells, mitochondria, animals, mice, inbred c57bl, humans, mice, carcinoma, hepatocellular, liver neoplasms, reactive oxygen species, perhexiline, carnitine o-palmitoyltransferase, linoleic acid, ppar alpha, enzyme inhibitors, apoptosis, up-regulation, models, biological, carcinogenesis, non-alcoholic fatty liver disease
13 authors
From US, KR
- Zachary J. BrownNational Institutes of Health; National Cancer Institute; Center for Cancer Research
- Qiong FuNational Institutes of Health; National Cancer Institute; Center for Cancer Research
- Chi MaNational Institutes of Health; National Cancer Institute; Center for Cancer Research
- Michael J. KruhlakNational Institutes of Health; National Cancer Institute; Center for Cancer Research
- Haibo ZhangNational Institutes of Health; National Cancer Institute; Center for Cancer Research
- Ji LuoNational Institutes of Health; National Cancer Institute; Center for Cancer Research
Abstract
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 β-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-α). 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.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY).
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