Phosphotidylethanolamines

Phosphatidylethanolamines (PE) are a class of phospholipids composed of a glycerol backbone, two fatty acyl chains, and a phosphate group combined with an ethanolamine head group. PE is synthesized through four independent pathways in eukaryotic cells: the CDP-ethanolamine or Kennedy pathway, acylation of Lyso-PE, the Phosphatidylserine Decarboxylase (PSD) Pathway, and head group base exchange¹. While these synthesis pathways occur in the endoplasmic reticulum (ER), the PSD pathway utilizes a catalytic triad composed of Asp-His-Ser anchored to the mitochondrial membrane. Phosphatidylserine decarboxylation and auto-cleavage result in an α subunit and a β subunit, which are required for enzymatic activity that leads to the enrichment of PE in the mitochondrial inner membrane. This pathway is also relevant to bacterial membranes.

PE, along with phosphatidylcholine (PC), are the most abundant phospholipids found in mammalian cells, with PE comprising 15-25% of total phospholipids in cellular membranes. PE is involved in numerous aspects of cellular function and is a critical component of mitochondrial membranes. These include maintaining the structural integrity of cell membranes, folding of membrane proteins, membrane fusion, protein biogenesis, oxidative phosphorylation, protein trafficking, autophagy, and mitochondrial function and stability. Furthermore, PE can be shuttled to other cellular compartments and serve as a precursor of other lipids and fatty acids with important physiological roles¹.

Emerging research has strongly focused on impairments in phospholipid metabolism and their impact on physiology and disease. Alterations in PE levels, PE metabolism, and PC/PE ratio are linked to the pathophysiology of age-related neurodegenerative diseases such as Parkinson’s Disease (PD) and Alzheimer’s Disease (AD). Moreover, PE’s role in maintaining critical cellular functions has been implicated in metabolic disorders (e.g., obesity, type-2 diabetes), liver disease, and cardiovascular disease.

Phosphatidylethanolamine, Mitochondrial Function, and Neurodegenerative Diseases

Parkinson’s disease is a debilitating motor disorder linked to the degeneration of dopaminergic neurons. Recent data have associated PD with the accumulation of α-synuclein, an important molecule that facilitates neurotransmission, which ultimately leads to cell death. While α-synuclein accumulation is mostly cytosolic, it associates with lipid rafts, a critical membrane structure partly regulated by PE. In one report utilizing yeast cells and worm models of PD, results demonstrated that PE deficiency significantly exacerbates neurodegeneration and cell death. This study showed that the alteration of PE levels induces ER stress and disrupts vesicle trafficking, leading to an accumulation of α-synuclein. Collectively, these factors accelerate neurodegeneration and cell death. Interestingly, the application of the PE precursor, ethanolamine, partially alleviates ER stress and restores cell growth². The importance of PE in cell biology extends to its involvement in various cellular pathways and the pathogenesis of numerous diseases.

Changes in lipid metabolism has also been linked to Alzheimer’s Disease, an age-related neurodegenerative disease characterized by the accumulation of amyloid-β plaques and severe cognitive decline. One report found that aberrant serum levels of phospholipids, including PE and lyso-PE, are correlated with AD severity and can serve as blood biomarkers that predicts disease progression from mild cognitive impairment to AD³. Other investigations have shown that PE’s role in oxidative stress also impacts AD development, where structural modifications in PE and decreases in PE levels contribute to an increase in free radicals, leading to exacerbated cell damage⁴.

Phosphatidylethanolamine in Oncology

Alterations in lipid metabolism play a critical role in numerous cancers, and lipid synthesis during cancer cell proliferation and development has emerged as a promising target for cancer therapeutics. Notably, phospholipids, including PE, that are transported to the outer membrane during apoptosis and oxidative stress are a promising biomarker for cancer diagnosis and disease monitoring. Indeed, previous findings have demonstrated that PE not only increases in apoptotic cells but also becomes exposed on the vascular endothelium of multiple types of tumors⁵.

PE promotes membrane fusion by stabilizing non-lamellar intermediate structures in the fusion process, which is relevant to cancer cell behavior as it can influence membrane dynamics and protein integration.

One report applied radiotracers targeting PE to examine the potential for non-invasive imaging and identification of apoptotic cells. These results demonstrated that 18F-duramycin successfully binds to PE and can be used to track both early and late-stage apoptosis during cancer⁶. Others have demonstrated that targeting PE pathways not only has diagnostic potential but could also be a target for cancer therapeutics. For example, one study investigating SMAC/Diablo, a pro-apoptotic protein that is overexpressed in cancer cell proliferation and development, demonstrated that this mechanism impacts PE synthesis by silencing PSD. This report further showed that downregulation of SMAC/Diablo leads to an increase in mitochondrial PE and inhibits cancer cell proliferation⁷. Collectively, these data provide evidence for PE and PE pathways as a promising target for cancer treatment.

Phosphatidylethanolamine in Metabolic Health

Impairments in lipid metabolism are a hallmark of metabolic diseases such as obesity and type-2 diabetes. Deviations in healthy lipid metabolism are characterized by hyperlipidemia, or an imbalance in cholesterol and triglyceride levels. These changes in lipid homeostasis lead to deleterious outcomes, including impaired glucose metabolism and decreased insulin sensitivity. Unsurprisingly, phospholipid metabolism is also impacted by metabolic disorders, and lipidomic mass spectrometry studies have identified decreases in PE as a potential biomarker for obesity and type-2 diabetes development8.

PE plays a crucial role in determining the structure and function of membrane proteins, and its altered metabolism can impact protein topology, potentially contributing to diseases such as Alzheimer’s and Parkinson’s.

For example, one study examining obese and insulin-resistant individuals found significant adipocyte atrophy and macrophage infiltration. Interestingly, these findings were accompanied by decreases in PEMT and increases in PE, inflammatory cytokines, and insulin resistance. These results provide evidence for aberrant PE metabolism in metabolic disorders as a compensatory mechanism for adipocyte-related inflammation and atrophy9.

Phosphatidylethanolamine in Liver Health

The pathophysiology of liver diseases, such as non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease, have a strong association with changes in lipid metabolism. While absolute levels of PE are important indicators of liver health, the ratio between PC and PE has been identified as a sensitive biomarker for liver disease progression, liver failure, and impaired liver regeneration¹⁰.

In liver cells, PE is localized and functions within the inner mitochondrial membrane, playing a crucial role in maintaining mitochondrial integrity and function.

For example, deletion of genes associated with phosphatidylethanolamine N-methyltransferase (PEMT), the primary enzyme that converts PE to PC, not only leads to a decrease in the PC/PE ratio but also results in non-alcoholic steatohepatitis (NASH)¹¹. Furthermore, the PC/PE ratio has potential as a biomarker that predicts survival following surgery—one report demonstrated that decreases in the PC/PE ratio are correlated with reduced survival rates after hepatic surgery¹². Similarly, increased alcohol intake observed in alcoholic fatty liver disease leads to alterations in PEMT processes. One study demonstrated that chronic alcohol intake leads to changes in methionine homeostasis, which subsequently results in inhibition of PEMT and decreased hepatic PC/PE ratio¹³.

Phosphatidylethanolamine and Cardiovascular Health

Metabolic disorders and hyperlipidemia are leading risk factors for cardiovascular disease (CVD). Considering the importance of PE in regulating lipid metabolism and cellular function, emerging research has identified decreases in PE and alterations in the PC/PE ratio as potential biomarkers for CVD pathology.

One report examining changes in phospholipid composition in red blood cells found that patients with coronary artery disease exhibit decreases in PC, but not PE. The alterations to the ethanolamine pathway and subsequent change in the PC/PE ratio resulted in compensatory increases in sphingomyelins. Taken together, these data suggest that metabolic changes due to age or lifestyle factors alter phospholipid composition and increase the risk for age-related diseases like CVD¹⁴.

Others have demonstrated that inflammation-associated lipid perturbations are linked to the remodeling of the left ventricle of the heart. This occurs through activation of the NLRP3 inflammasome, a critical mediator of chronic inflammation in obesity-related diseases like CVD. These data revealed that individuals with CVD and insulin resistance show a decrease in the PC/PE ratio, which is also correlated with increased NLRP3 and significant left ventricle remodeling. Overall, these findings provide further evidence for phospholipids like PE and PC as promising biomarkers for CVD risk and insulin resistance¹⁵.

Phosphatidylethanolamine and Research

As of July 2024, there are over 28,000 citations for phosphatidylethanolamine in research publications (excluding books and documents) on Pubmed. The large number of publications linking this metabolite to a broad range of physiological functions suggests that any research program seeking to better understand neurological, oncological, liver, metabolic, and cardiovascular health may benefit from quantitative analysis of phosphatidylethanolamine. Considering the importance of phosphatidylethanolamine in biological functions, preclinical research may also benefit from phosphatidylethanolamine quantification to further the understanding of biomarkers, diagnosis, and disease.