Repurposing a tricyclic antidepressant in tumor and metabolism disease treatment through fatty acid uptake inhibition

by Selleckchem | Nov 12 2023

Fatty acid uptake is essential for cell physiological function, but detailed mechanisms remain unclear. Here, we generated an acetyl-CoA carboxylases (ACC1/2) double-knockout cell line, which lacked fatty acid biosynthesis and survived on serum fatty acids and was used to screen for fatty acid uptake inhibitors. We identified a Food and Drug Administration-approved tricyclic antidepressant, nortriptyline, that potently blocked fatty acid uptake both in vitro and in vivo. We also characterized underlying mechanisms whereby nortriptyline provoked lysosomes to release protons and induce cell acidification to suppress macropinocytosis, which accounted for fatty acid endocytosis. Furthermore, nortriptyline alone or in combination with ND-646, a selective ACC1/2 inhibitor, significantly repressed tumor growth, lipogenesis, and hepatic steatosis in mice. Therefore, we show that cells actively take up fatty acids through macropinocytosis, and we provide a potential strategy suppressing tumor growth, lipogenesis, and hepatic steatosis through controlling the cellular level of fatty acids.

Comments:

The passage you provided describes a study in which researchers investigated the mechanisms of fatty acid uptake by cells and identified a potential inhibitor of this process. Here's a breakdown of the key findings and implications of the study:

1. **Fatty Acid Uptake and Cell Physiology**: Fatty acids are essential molecules for various cellular functions. Cells can either synthesize fatty acids themselves or take them up from their environment. The detailed mechanisms of how cells take up fatty acids were not well understood prior to this study.

2. **Generation of ACC1/2 Double-Knockout Cell Line**: The researchers created a cell line in which both acetyl-CoA carboxylases (ACC1 and ACC2) were knocked out. ACC1 and ACC2 are enzymes involved in fatty acid biosynthesis. By knocking out these enzymes, the cells were unable to synthesize their own fatty acids and had to rely on external sources, such as serum fatty acids, for survival.

3. **Identification of Nortriptyline as an Inhibitor**: The study identified nortriptyline, a tricyclic antidepressant that is approved by the Food and Drug Administration (FDA), as a potent inhibitor of fatty acid uptake. Nortriptyline was found to block fatty acid uptake both in laboratory cell cultures (in vitro) and in living organisms (in vivo).

4. **Mechanism of Action**: The researchers investigated how nortriptyline inhibited fatty acid uptake. They found that nortriptyline induced lysosomes (organelles within cells) to release protons, leading to increased acidity within the cell. This acidification of the cell environment was shown to suppress macropinocytosis, a process by which cells engulf and take in large molecules or particles from their surroundings. Macropinocytosis was identified as the mechanism by which cells were taking up fatty acids.

5. **Therapeutic Potential**: Nortriptyline, either alone or in combination with ND-646 (a selective ACC1/2 inhibitor), was found to have significant therapeutic potential. It suppressed tumor growth, lipogenesis (the production of fats), and hepatic steatosis (accumulation of fat in the liver) in mice. This suggests that controlling the cellular level of fatty acids, either by inhibiting fatty acid uptake or by inhibiting fatty acid synthesis, could be a strategy to combat conditions like cancer and liver disease.

In summary, this study sheds light on the mechanisms of fatty acid uptake by cells and identifies nortriptyline as a potential inhibitor of this process. The findings have implications for understanding cellular physiology and offer a potential therapeutic approach for conditions involving abnormal fatty acid metabolism.