Metabolic Regulation of Fibroblast Activation and Proliferation during Organ Fibrosis

Abstract

Background: Activated fibroblasts are present in the injury response, tumorigenesis, fibrosis, and inflammation in a variety of tissues and myriad disease types.

Summary: During normal tissue repair, quiescent fibroblasts transform into a proliferative and contractile phenotype termed myofibroblasts and are then lost as repair resolves to form a scar. When excessive levels are reached, activated fibroblasts proliferate and produce large amounts of extracellular matrix, which accumulates in the interstitial space of different organs. This accumulation leads to fibrotic dysfunction and multiple-organ dysfunction syndrome. To date, there are limited effective treatments for these conditions. Cellular metabolism is the cornerstone of all biological activities. Emerging evidence shows that metabolic alterations in fibroblasts are important for the activation process and illness progression. These discoveries, along with current clinical advances showing decreased lung fibrosis after targeting specific metabolic pathways, thus offer new possibilities for therapeutic interventions. The purpose of this review was to summarize the most recent knowledge of the major metabolic changes that occur during fibroblast transition from quiescent to activated states and the evidence linking alterations in fibroblast metabolism to the pathobiology of several common fibrotic diseases and tumor-related diseases.

Key messages: Metabolic disorders are associated with the progression of chronic kidney diseases. Interfering with fibroblast metabolism may be a promising therapeutic strategy for renal fibrosis and other fibrosis-related diseases.

Keywords: Fibroblast activation; Fibroblast proliferation; Metabolic pathways; Renal fibrosis.

Fig. 1

Examples of fibrosis-related diseases. NASH, nonalcoholic steatohepatitis.

Fig. 2

Major metabolic pathways in fibroblasts. Glycolysis is a 10-step series of reaction that converts glucose into pyruvate; pyruvate is then converted into lactate or enters the TCA cycle as acetyl-CoA to eventually generate ATP. Metabolic intermediates derived from glycolysis such as G-6-P can also be diverted to the PPP to generate NADPH and nucleotides. While 3-PG convert to serine/glycine metabolism in a three-step enzymatic reaction including the enzymes in order; PHGDH, PSAT1, and PSPH. Serine then fuels glycine synthesis via two SHMT genes; SHMT1 and SHMT2, producing collagen accounting for fibrosis. Fatty acids are metabolized in mitochondria via β-oxidation, yielding large amounts of NADH and FADH2 for ATP synthesis. In addition, activated fibroblasts also utilize glutaminolysis for promoting profibrotic activities via the conversion of glutamine to α-KG. Intermediate products of TCA cycle can synthesize amino acids for stabilizing collagen structure. GLUT, glucose transporter; G6PDH, glucose-6-phosphate dehydrogenase; 6GPDH, 6-phosphogluconate dehydrogenase; LDH, lactate dehydrogenase; NAD⁺/NADH, nicotinamide adenine dinucleotide; ADP, adenosine diphosphate; ATP, adenosine triphosphate; MPC, mitochondrial pyruvate carrier; OAA, oxaloacetate; SucCoA, succinyl CoA; α-KG, α-ketoglutarate; PHGDH, phosphoglycerate dehydrogenase; PSAT1, phosphoserine aminotransferase; PSPH, phosphoserine phosphatase; SHMT, serine hydroxymethyltransferase.