Carnitine palmitoyltransferase gene upregulation by linoleic acid induces CD4+ T cell apoptosis promoting HCC development

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.

Dysregulation of metabolic pathways by carnitine palmitoyl-transferase 1 plays a key role in central nervous system disorders: experimental evidence based on animal models

“…Inhibition of CPT1 by etomoxir has been shown to downregulate the production of reactive oxygen species 60 . We found a tendency towards a decreased gene expression of Nox-2 and Ho-1 in the hindbrain in the EAE models following downregulation of CPT1, and CPT1A ( Fig.…”

Tri-Herbal Medicine Divya Sarva-Kalp-Kwath (Livogrit) Regulates Fatty Acid-Induced Steatosis in Human HepG2 Cells through Inhibition of Intracellular Triglycerides and Extracellular Glycerol Levels

“…This apparent normalization of CPT1A levels post SKK treatment points towards a chain of events leading to the attainment of homeostasis by the cells [ 58 , 59 ]. Prolonged enhancement of CPT1A activity can lead to increased mitochondrial energy metabolism leading to heightened reactive oxygen species generation and causing cellular damage and apoptosis [ 60 ]. Whereas, a decrease in CPT1A expression can lead to reduced β-oxidation in liver and could contribute to fatty acid accumulation and inflammation in hepatocytes [ 61 ].…”

Proteomics Reveals that Methylmalonyl-CoA Mutase Modulates Cell Architecture and Increases Susceptibility to Stress

“…While defects of CPT2 are often causative of fatty acid oxidation disorders [42], its upregulation may probably reflect the demand of delivering long-chain fatty acids to the mitochondrial matrix as fuel for the cell; in concordance, the upregulation of SLC27A4 and DECR1 may suggest an increased rate in fatty acid oxidation. Furthermore, the upregulation of CPT2 was found to increase ROS, contributing to cellular damage [43]. The upregulation of NUDT19 may be linked to an increase in the hydrolysis of fatty acyl-CoA esters.…”