Using Dictyostelium to Advance Our Understanding of the Role of Medium Chain Fatty Acids in Health and Disease.

Erwann Pain,Robin S B Williams,Sonia Shinhmar

doi:10.3389/fcell.2021.722066

Erwann Pain, Robin S B Williams + Show 1 more

Open Access

https://doi.org/10.3389/fcell.2021.722066

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Abstract

Ketogenic diets have been utilized for many years to improve health, and as a dietary approach for the treatment of a range of diseases, where the mechanism of these low carbohydrate and high fat diets is widely considered to be through the production of metabolic products of fat breakdown, called ketones. One of these diets, the medium chain triglyceride ketogenic diet, involves high fat dietary intake in the form of medium chain fatty acids (MCFAs), decanoic and octanoic acid, and is commonly used in endurance and high intensity exercises but has also demonstrated beneficial effects in the treatment of numerous pathologies including drug resistant epilepsy, cancer, and diabetes. Recent advances, using Dictyostelium discoideum as a model, have controversially proposed several direct molecular mechanisms for decanoic acid in this diet, independent of ketone generation. Studies in this model have identified that decanoic acid reduces phosphoinositide turnover, diacylglycerol kinase (DGK) activity, and also inhibits the mechanistic target of rapamycin complex 1 (mTORC1). These discoveries could potentially impact the treatment of a range of disorders including epilepsy, cancer and bipolar disorder. In this review, we summarize the newly proposed mechanisms for decanoic acid, identified using D. discoideum, and highlight potential roles in health and disease treatment.

Highlights

In our modern societies, fats are often considered to be damaging to health, with more than half of the European population considered overweight, and with cardiovascular diseases caused by obesity providing the most common cause of death in rich countries (Abdelaal et al, 2017)
This study provided a pivotal breakthrough in the identification of decanoic acid as reproducing the bioactivity of valproic acid (VPA) in a more potent manner (Figure 1), that may impact on seizure control since it is a key component of the medium chain triglyceride (MCT) ketogenic diet (Augustin et al, 2018a), and it is elevated in the plasma of patients on the MCT ketogenic diet (Huttenlocher et al, 1971; Haidukewych et al, 1982; Sills et al, 1986a,b)
This D. discoideumbased research suggests that VPA, lithium and specific medium chain fatty acids (MCFAs) including decanoic acid may function in the treatment of bipolar disorder through effects on diacylglycerol kinase (DGK)

Summary

INTRODUCTION

Fats are often considered to be damaging to health, with more than half of the European population considered overweight, and with cardiovascular diseases caused by obesity providing the most common cause of death in rich countries (Abdelaal et al, 2017). Chronic treatment with VPA, or lithium, or specific MCFAs including decanoic acid, blocked multicellular development, and this effect was lost in the DGKA- mutant These compounds triggered an increase in DAG levels in wild type cell, but not in DGKA- cells (Kelly et al, 2018), where metabolic changes in the mutant were suggested to bypass DGKA and remove sensitivity to pharmacological inhibition of the enzyme by these compounds. This D. discoideumbased research suggests that VPA, lithium and specific MCFAs including decanoic acid may function in the treatment of bipolar disorder through effects on DGK. The diet increased plasma levels of decanoic acid by 24–28-fold (in children and adults), and provided a 50% reduction in mean frequency of seizures/events, correlating with decanoic acid levels, despite absent or very low levels of ketosis (Schoeler et al, 2021)

CONCLUSION

Findings

AUTHOR CONTRIBUTIONS