Suppressed de novo lipogenesis by plasma membrane citrate transporter inhibitor promotes apoptosis in HepG2 cells

Suppression of the expression or activities of enzymes that are involved in the synthesis of de novo lipogenesis (DNL) in cancer cells triggers cell death via apoptosis. The plasma membrane citrate transporter (PMCT) is the initial step that translocates citrate from blood circulation into the cytoplasm for de novo long‐chain fatty acids synthesis. This study investigated the antitumor effect of the PMCT inhibitor (PMCTi) in inducing apoptosis by inhibiting the DNL pathway in HepG2 cells. The present findings showed that PMCTi reduced cell viability and enhanced apoptosis through decreased intracellular citrate levels, which consequently caused inhibition of fatty acid and triacylglycerol productions. Thus, as a result of the reduction in fatty acid synthesis, the activity of carnitine palmitoyl transferase‐1 (CPT‐1) was suppressed. Decreased CPT‐1 activity also facilitated the disruption of mitochondrial membrane potential (ΔΨm) leading to stimulation of apoptosis. Surprisingly, primary human hepatocytes were not affected by PMCTi. Increased caspase‐8 activity as a consequence of reduction in fatty acid synthesis was also found to cause disruption of ΔΨm. In addition, apoptosis induction by PMCTi was associated with an enhanced reactive oxygen species generation. Taken together, we suggest that inhibition of the DNL pathway following reduction in citrate levels is an important regulator of apoptosis in HepG2 cells via suppression of CPT‐1 activity. Thus, targeting the DNL pathway mediating CPT‐1 activity by PMCTi may be a selective potential anticancer therapy. Upregulation of the de novo lipogenesis (DNL) pathway is metabolic hallmark for cancer cells. Citrate, transported by the plasma membrane citrate transporter (PMCT), serves as an important precursor for DNL. In this study, we demonstrate that in HepG2 cells, a PMCT inhibitor (PMCTi) blocks the DNL pathway causing an accumulation of malonyl‐CoA. This has an inhibitory effect on carnitine palmitoyl transferase‐1 activity, an inducer of mitochondrial‐dependent apoptosis. Surprisingly, PMCTi treatment had no apoptosis effect in normal hepatocytes. Thus, targeting the DNL pathway by PMCTi may be a selective potential therapeutic agent for HepG2 cells.