Metabolic reprogramming in the pathogenesis of chronic lung diseases, including BPD, COPD, and pulmonary fibrosis

Abstract

The metabolism of nutrient substrates, including glucose, glutamine, and fatty acids, provides acetyl-CoA for the tricarboxylic acid cycle to generate energy, as well as metabolites for the biosynthesis of biomolecules, including nucleotides, proteins, and lipids. It has been shown that metabolism of glucose, fatty acid, and glutamine plays important roles in modulating cellular proliferation, differentiation, apoptosis, autophagy, senescence, and inflammatory responses. All of these cellular processes contribute to the pathogenesis of chronic lung diseases, including bronchopulmonary dysplasia, chronic obstructive pulmonary disease, and pulmonary fibrosis. Recent studies demonstrate that metabolic reprogramming occurs in patients with and animal models of chronic lung diseases, suggesting that metabolic dysregulation may participate in the pathogenesis and progression of these diseases. In this review, we briefly discuss the catabolic pathways for glucose, glutamine, and fatty acids, and focus on how metabolic reprogramming of these pathways impacts cellular functions and leads to the development of these chronic lung diseases. We also highlight how targeting metabolic pathways can be utilized in the prevention and treatment of these diseases.

Keywords: bronchopulmonary dysplasia; chronic obstructive pulmonary disease; metabolic flexibility; metabolic reprogramming; pulmonary fibrosis.

Fig. 1.

Glucose catabolism. Upon transport into the cell, glucose is subject to the following two major pathways for metabolism: glycolysis and the pentose phosphate pathway (PPP), in which G6P appears at the crossroads of these pathways. There are three rate-limiting steps, catalyzed by hexokinase (HK), phosphofructokinase (PFK), and pyruvate kinase (PK), which converts glucose into pyruvate. Glycolysis is a major pathway for glucose metabolism, in which pyruvate can be converted into lactate by lactate dehydrogenase (LDH) or be transported into mitochondria by mitochondrial pyruvate carrier (MPC) to fuel ATP production by oxidative phosphorylation through the electron transport chain (ETC). The PPP divides into the oxidative and nonoxidative branches, which the oxidative branch generates reducing equivalents in the form of NAPDH, while the nonoxidative branch produces ribose-5-phosphate (R5P). The PPP can feed back glycolysis at the levels of glyceraldehyde 3-phosphate (3PG) and fructose-6-phosphate (F6P) (solid arrows). The 3PG metabolite can be used for the de novo synthesis of serine and glycine, which provides the essential precursors for the synthesis of proteins, nucleic acids, and lipids (dashed arrows). 6PG, 6-phosphogluconate; 3PHP, 3-phosphohydroxypyruvate; 3PS, 3-phosphoserine; F-1,6-BP, fructose-1,6-biphosphate; PEP, phosphoenolpyruvate; PHGDH, phosphoglycerate dehydrogenase; PSAT, phosphoserine aminotransferase; SHMT, serine hydroxymethyltransferase; TCA, tricarboxylic acid; G6PD, glucose-6-phosphate dehydrogenase; 6PGD, 6-phosphogluconate dehydrogenase.

Fig. 2.

Fatty acid uptake, activation, and oxidation. Long-chain fatty acids (FAs) disassociated from albumin (Alb) or lipoproteins can enter cells via specific transport proteins (e.g., FATP and CD36/FABPpm). Once inside the cell, long-chain FAs are catalyzed and activated by fatty acyl-CoA synthetases (ACS) to form fatty acyl-CoA, which is then ready for storage in lipid droplets (LDs) as neutral lipids (e.g., triglycerides). Under metabolic stress or nutrient deprivation, FAs are released from LDs through lipolysis or lipophagy for energy generation by β-oxidation and tricarboxylic acid (TCA) cycle in the mitochondria. Unlike short- and medium-chain FAs, long-chain FAs require the carnitine shuttle system to be transported into mitochondrion for β-oxidation. Cpt1 (mainly Cpt1a) is the first component and rate-limiting step of the carnitine shuttle system, which catalyzes the transfer of the acyl group of LCFAs from coenzyme A (CoA) to carnitine to form acylcarnitine.

Fig. 3.

Simplified schematic of TCA cycle and its metabolites producing NADPH. TCA cycle is composed of a series of chemical reactions used to release stored energy in the form of ATP from major nutrient substrates, including glucose, glutamine, and fatty acids. Acetyl-CoA is the starting point of TCA cycle, which can be generated by pyruvate dehydrogenase from pyruvate or by fatty acid β-oxidation. Glutamate generated from glutaminolysis can be converted into α-ketoglutarate (α-KG) and then participates in the TCA cycle. TCA-derived citrate can be transported into cytosol for producing pyruvate and glutamate with the generation of NADPH. Cytosol citrate can be catalyzed by acetyl-CoA ligase (ACL) to generate acetyl CoA, which is utilized for the creation of fatty acids along with NADPH. Solid arrows denote the steps of TCA cycle, whereas dashed arrows denote the generation of fatty acids and glutamine from glucose-derived citrate. ME, malic enzyme; IDH, isocitrate dehydrogenase.