Metabolic requirements of pulmonary fibrosis: role of fibroblast metabolism

Abstract

Fibrosis is a pathologic condition characterized by excessive deposition of extracellular matrix and chronic scaring that can affect every organ system. Organ fibrosis is associated with significant morbidity and mortality, contributing to as many as 45% of all deaths in the developed world. In the lung, many chronic lung diseases may lead to fibrosis, the most devastating being idiopathic pulmonary fibrosis (IPF), which affects approximately 3 million people worldwide and has a median survival of 3.8 years. Currently approved therapies for IPF do not significantly extend lifespan, and thus, there is pressing need for novel therapeutic strategies to treat IPF and other fibrotic diseases. At the heart of pulmonary fibrosis are myofibroblasts, contractile cells with characteristics of both fibroblasts and smooth muscle cells, which are the primary cell type responsible for matrix deposition in fibrotic diseases. Much work has centered around targeting the extracellular growth factors and intracellular signaling regulators of myofibroblast differentiation. Recently, metabolic changes associated with myofibroblast differentiation have come to the fore as targetable mechanisms required for myofibroblast function. In this review, we will discuss the metabolic changes associated with myofibroblast differentiation, as well as the mechanisms by which these changes promote myofibroblast function. We will then discuss the potential for this new knowledge to lead to the development of novel therapies for IPF and other fibrotic diseases.

Keywords: bioenergetics; fibroblast; metabolism; mitochondria; pulmonary fibrosis.

Figure 1.. Glycolysis promotes biosynthetic reactions required for myofibroblast differentiation.

Increased glycolysis downstream of TGF-β allows for the diversion of metabolites into biosynthetic pathways including the Pentose Phosphate Pathway (PPP), the Hexosamine Biosynthesis Pathway (HBP), and the Serine-Glycine Synthesis Pathway. The PPP promotes production of nucleotides as well as NADPH which protects cells from increased ROS levels. The HBP is essential for protein glycosylation and GlcNAcylation. The de novo synthesis of glycine is required for collagen protein synthesis as glycine constitutes one-third of all amino acids in collagen protein. Mitochondria-produced citrate is an important substrate for fatty acid synthesis, which also promotes myofibroblast differentiation. Glutamine metabolism is required for anaplerosis of the TCA cycle as well as for production of proline, the second-most abundant amino acid found in collagen protein.

Figure 2.. Both glucose and glutamine metabolism contribute to glycine synthesis in myofibroblasts.

TGF-β induces the expression of the enzymes of the Serine-Glycine Synthesis Pathway in lung fibroblasts. These enzymes convert the glycolytic intermediate 3-phosphoglycerate into the amino acids, serine and glycine. Carbon from glucose is incorporated into glycine and thus into collagen protein. PSAT1 (phosphoserine aminotransferase 1) catalyzes the transfer of the alpha amino group from glutamine-derived glutamate to 3-phosphohydroxypyruvate, producing 3-phosphoserine. Carbon from glutamine is not incorporated into glycine; glutamine metabolism contributes nitrogen to promote glycine synthesis.

Figure 3.. Transcription Factors activated by TGF-β promote metabolic reprogramming in lung fibroblasts and myofibroblast differentiation.

Canonical signaling downstream of TGF-β promotes myofibroblastic differentiation and matrix protein production in lung fibroblasts through activation of SMAD transcription factors. Non-canonical pathways lead to activation of HIF-1α and ATF4 which promote glycolytic metabolism and de novo amino acid biosynthesis, respectively. Inhibition of PPARγ downstream of TGF-β is required for myofibroblast differentiation through poorly understood mechanisms, likely involving the effects of PPARγ on fatty acid metabolism.