Fibrosis is characterized by excessive extracellular matrix (ECM) production relative to catabolism. A new study shows that the fuel choice of fibroblasts impacts this balance, with glycolysis promoting ECM synthesis and fatty acid oxidation stimulating ECM degradation.
Excessive biomolecule synthesis (anabolism) relative to breakdown (catabolism) is an important cause of disease, as is evident in obesity, cancer, and fibrosis. Skin fibrosis occurs as a result of exaggerated healing response, leading to pathological accumulation of ECM compromising the function and architecture of the dermis1. To prevent fibrosis, ECM anabolism and catabolism need to be aligned and tightly controlled. Writing in this issue of Nature Metabolism, Zhao et al.2 report that glycolysis and fatty oxidation have opposing effects on this balance in skin fibroblasts.
To establish the connection between fibrosis and metabolism, Zhao et al.2 examined transcriptional changes in fibrotic skin and observed upregulation of glycolytic and downregulation of fatty acid oxidation genes in radiation-induced skin fibrosis in mice and, impressively, in human specimens. In line with these observations, in vitro activation of primary human dermal fibroblasts favoured the expression of glycolytic genes and suppressed genes associated with the oxidation of fatty acids. Strikingly, genetic and pharmacological manipulations that impaired glycolysis tended to decrease fibroblast ECM production, whereas those suppressing fatty acid oxidation had the opposite effect. Thus, the activity of fuel-utilization pathways seems to exert control over ECM homeostasis (Fig. 1).
Why would glycolysis promote anabolism and fatty acid oxidation promote catabolism? Photosynthetic organisms can engage in pure anabolism, building biomass from carbon dioxide. In non-photosynthetic organisms, however, anabolism must always be coupled with catabolism, which generates energy and carbon building blocks for biosynthesis. In aerobic conditions, both glucose and fat are excellent sources of energy. Glucose differs from fat, however, in enabling anaerobic energy production and in being a superior precursor for synthesizing biomass building blocks. Although bacteria, yeast, and plants can convert two-carbon units made from fat into larger carbon skeletons using the glyoxylate shunt, animals lack this pathway. Accordingly, animal cells cannot make nucleotides or amino acids from fat and require glucose for these purposes. Consistent with glucose being an important biosynthetic precursor, upregulation of glycolysis is closely associated with cell growth, for example in cancer cells and in activated T cells3,4.
To support ECM production, fibroblasts have high glycolytic flux and biosynthetic activity even when not growing5. The most abundant ECM protein is collagen, which is highly enriched in the amino acid glycine. Glycine can be produced from glucose via the serine–glycine one-carbon pathway, with inhibitors of the serine biosynthetic enzyme phosphoglycerate dehydrogenase having antifibrotic activity6.
Although fatty acids cannot substitute for glucose as anabolic precursors, it is unclear why fatty acid degradation would suppress ECM build-up rather than merely provide an additional ATP source to support anabolic reactions. One possibility is that glycolysis runs better when other sources of ATP are limited. Another is that some fibroblasts are glycolytic and anabolic, while others depend on fatty acid oxidation and are net catabolic. This would mirror phenomena in the immune system, where fatty acid metabolism can support non-glycolytic, immunosuppressive T cells7.
In such a scenario, the key role of fatty acid oxidation may be to support ECM catabolism by fibroblasts. Consistent with this, Zhao et al.2 show that in cultured fibroblasts, a small molecule called caffeic acid both induces fatty acid oxidation genes and lysosomes, leading to ECM catabolism. These effects appear to be mediated by caffeic acid activating peroxisome proliferator–activated receptor (PPAR) signalling, consistent with previous data showing that PPAR activators have anti-fibrotic activity8.
Such a model depends on the physiological relevance of fibroblasts in ECM catabolism, a function normally attributed to macrophages. Zhao et al.2 provide two lines of evidence supporting a potential role for fibroblast ECM catabolism in limiting fibrosis. First, caffeic acid phenylethyl ester (CAPE) has in vivo anti-fibrotic activity. However, this was previously known and may occur via mechanisms unrelated to fatty acid oxidation or fibroblast ECM catabolism9,10. Second and more persuasively, building on evidence that the fatty acid translocase CD36 can bind collagen11, Zhao et al.2 show that implantation of CD36hi fibroblasts from adipose depots into fibrotic skin mitigated collagen build-up and associated leg contractures (Fig. 1). Collectively, these observations suggest a link between fibroblast fatty acid oxidation and ECM catabolism.
The described work is part of a growing literature examining the potential of targeting cellular metabolism to treat ‘non-metabolic’ conditions. While the majority of metabolic studies in fibrosis have focused on fibroblasts5,6, the development of fibrosis also involves epithelial cells and infiltrating immune cells. Both keratinocytes12 and macrophages13 upregulate glycolysis during wound healing. Therefore, targeting glycolysis will not only affect fibroblast ECM production, but it may also inhibit the proliferation and differentiation of keratinocytes and alter the function of macrophages. The consequences of such changes remain unclear.
Further exploration is critical, because at present limited therapeutic options exist for organ fibrosis, which contributes to up to one-third of deaths worldwide through diseases such as cirrhosis and idiopathic pulmonary fibrosis14. Skin fibrosis itself is caused by a wide spectrum of conditions, including scleroderma and graft-versus-host disease, as well as trauma, burns, and radiation1. The radiation-induced skin fibrosis studied by the authors is a relatively rare long-term complication of cancer radiation therapy15. With further mechanistic understanding and generalization to other fibrotic conditions, however, this line of research could have a huge clinical impact.