The role of fatty acid metabolism in acute lung injury: a special focus on immunometabolism

Abstract

Reputable evidence from multiple studies suggests that excessive and uncontrolled inflammation plays an indispensable role in mediating, amplifying, and protracting acute lung injury (ALI). Traditionally, immunity and energy metabolism are regarded as separate functions regulated by distinct mechanisms, but recently, more and more evidence show that immunity and energy metabolism exhibit a strong interaction which has given rise to an emerging field of immunometabolism. Mammalian lungs are organs with active fatty acid metabolism, however, during ALI, inflammation and oxidative stress lead to a series metabolic reprogramming such as impaired fatty acid oxidation, increased expression of proteins involved in fatty acid uptake and transport, enhanced synthesis of fatty acids, and accumulation of lipid droplets. In addition, obesity represents a significant risk factor for ALI/ARDS. Thus, we have further elucidated the mechanisms of obesity exacerbating ALI from the perspective of fatty acid metabolism. To sum up, this paper presents a systematical review of the relationship between extensive fatty acid metabolic pathways and acute lung injury and summarizes recent advances in understanding the involvement of fatty acid metabolism-related pathways in ALI. We hold an optimistic believe that targeting fatty acid metabolism pathway is a promising lung protection strategy, but the specific regulatory mechanisms are way too complex, necessitating further extensive and in-depth investigations in future studies.

Keywords: Acute lung injury; Fatty acid metabolism; Metabolic reprogram; Obesity.

Fig. 1

Main fatty acids metabolism pathway in lungs and alteration during acute lung injury. The metabolic process of fatty acids encompasses their cellular uptake and storage, transport to mitochondria, mitochondrial oxidation, and synthesis. Lung epithelial cells can uptake FAs from extracellular sources, including lipoproteins, free FAs, through a series of specialized transporters such as FABP, FATP, CD36, Caveolin-1 and FFAR. The intracellular sources of FAs include de novo fatty acid synthesis, lipolysis, lipophagy and hydrolysates of glycerol phospholipids. De novo fatty acid synthesis occurs in the cytoplasm, where citrate is converted to the final long-chain saturated or unsaturated FA. These steps are catalyzed by ACLY, ACC, FASN, and desaturases, as well as elongases. Subsequently, some FAs are stored in LDs in the form of triglycerides or mobilized through β-oxidation to generate energy and acetyl-CoA which returns to the TCA circle, while the other FAs are incorporated into cellular phospholipids and released from cell membranes to serve as important lipid mediators. During ALI, inflammation and oxidative stress lead to energy depletion, resulting in impaired fatty acid oxidation, increased expression of proteins involved in fatty acid uptake and transport, enhanced synthesis of fatty acids, and accumulation of LDs as well as up-regulated lipolysis

Fig. 2

Obesity reprograms fatty acid metabolism and exacerbates lung injury. In obese individuals, metabolic overload causes the increase of circulating FFAs, as well as leading to an upregulation of major proteins associated with fatty acid uptake and transport. Besides, obesity is a state of excessive LD accumulation, disordered lipolysis and chronic inflammation. Triglycerides accumulated in obese individuals are mainly originates from de novo fatty acid synthesis rather than other lipids. Furthermore, obesity leads to changes in fatty acid composition and their derivatives, including increased ω-6 fatty acids and decreased SPMs. All these metabolic alterations may further exacerbate ALI