The relationship between metabolic disease and alternations in lipid homeostasis

By Bhavana KunkalikarReviewed by Danielle Ellis, B.Sc.Jan 4 2023

In a recent review published in Advances in Food and Nutrition Research, researchers assessed the function of lipids in metabolic diseases.

Background

Lipids play an essential role in the proper functioning of the human body. In the past two decades, the understanding of the role of lipids has greatly evolved from an energy storage component to a crucial element in maintaining cell homeostasis. Hence, recent studies have focused on lipids as important compounds influencing human health.

Several pathological conditions that are characterized by changes in lipid metabolism have been described so far by researchers. This is especially true for metabolic disorders such as type 2 diabetes, steatosis, cardiovascular diseases, and cancer.

Lipid metabolism and lipotoxicity

Lipotoxicity and its significance

Lipotoxicity is described as the deleterious impact of the collection of fats and their corresponding metabolites in the vicinity of the adipose tissue. The elevated levels of lipids adversely affect cellular homeostasis while disrupting tissue function.

Studies have found that the main reason for lipotoxicity is high lipid intake. On the other hand, the inability of the human body to store fat within the adipose tissue, along with inefficient lipolysis, can also increase circulating fat concentrations. The main pathway here is that in the presence of excess circulating fat, adipocytes begin fat storage by increasing their size as well as the number of adipocytes.

Researchers have noted that inter-tissue communication pathways, which are responsible for energy homeostasis regulation, are altered during lipotoxicity. It is also found that the immune system and lipid metabolism are interconnected.

Hence, immunometabolic pathways are associated with lipotoxicity. Similarly, as lipotoxicity leads to inflammation, lipid metabolism changes can result in immune system alterations. This results in a vicious cycle that can lead to several chronic diseases.

Lipid metabolism and inflammation

Lipid metabolism is essential in inflammation regulation, especially with respect to chronic non-communicable disorders. This led to the development of novel nutritional therapies focusing on lipid metabolism to decrease inflammation and enhance the immune response during cardiovascular diseases, obesity, and autoimmune and metabolic disorders. Different lipid species function differently and have pro-inflammatory, immunomodulatory, and anti-inflammatory properties.

Studies have revealed that the accumulation of omega-6 fatty acid (FA)-associated lipids and saturated fatty acids (SFAs) facilitates inflammation. An association has been noted between the extent of unsaturation of polyunsaturated fatty acids (PUFAs) and their impact on inflammation as well as the immune system. Yet, it is now known that the degree of saturation itself is insufficient in determining the biological role of PUFAs.

Furthermore, higher levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) can disturb the homeostasis towards less inflammatory phenotypes. It has also been suggested that the ability of dietary FAs to act differently on distinct cells involved in the immune response that impact systemic inflammation can be employed to treat metabolic disorders.

Lipotoxicity and oxidative stress

Oxidative stress is described as the imbalance between the metabolism and production of reactive oxygen species (ROS). This imbalance leads to the appearance of oxidizing conditions, which could result in an increase in ROS. The inability to consume ROS eventually causes a free radical attack on carbohydrates, lipids, proteins, and nucleic acids that impact cellular functions and lead to death.

In metabolically active tissues like the heart and liver, excess SFAs solicit mitochondrial dysfunction, leading to reduced adenosine triphosphate (ATP) production and increased ROS generation. The production of mitochondrial ROS leads to the disruption of mitochondrial deoxyribonucleic Acid (DNA). This, in turn, impacts the electron transport chain and stimulates the initiation of the apoptosis process.

Lipotoxicity and metabolic reprogramming

Metabolic reprogramming is the ability of certain cells, like tumor cells, to alter their metabolism to satisfy high energy requirements, which may cause rapid growth and proliferation. Changes in lipid metabolism play an important role in the biology of tumor cells.

The primary modifications that are observed during tumor cell lipid metabolism are (1) biosynthesis followed by oxidation of FAs, (2) FA uptake, (3) storage and export of lipids, (4) lipolysis, and (5) the mevalonate pathway.

The enzymes involved in the metabolic processes are upregulated via activating the sterol regulatory element-binding proteins (SREBPs). The SREBPs are important transcription factors involved in lipid metabolism. Thus, tumor cells have several lipids playing different functions which facilitate the adaptation to adverse conditions while allowing growth at a high rate.

Furthermore, increased lipolysis is linked to cachexia, among the worst clinical cancer presentations. Many cytokines play a role in elevated lipolysis of tumoral cells. Notably, many tumor cell types exhibit higher β-oxidation and a higher expression of fatty oxidation enzymes. Additionally, increased FA oxidation facilitates a better response from tumor cells against oxidative stress.

Conclusion

The study findings highlighted the association of lipid metabolism with the correct function of a living organism. Lipid homeostasis can be achieved and maintained by observing a balance between the uptake, intake, and catabolism of lipids. While the loss of lipid homeostasis can cause several metabolic disorders via different molecular pathways, researchers believe that further studies are essential to understand the full mechanism involved in regulating lipid homeostasis.