Butyrate Prevents Tgf-Beta 1-Induced Alveolar Myofibroblast Differentiation And Modulates Energy Metabolism

Idiopathic pulmonary fibrosis (IPF) is a serious lung disease characterized by excessive collagen matrix deposition and extracellular remodeling. Signaling pathways mediated by fibrotic cytokine transforming growth factor beta 1 (TGF-beta 1) make important contributions to pulmonary fibrosis, but it remains unclear how TGF-beta 1 alters metabolism and modulates the activation and differentiation of pulmonary fibroblasts. We found that TGF-beta 1 lowers NADH and NADH/NAD levels, possibly due to changes in the TCA cycle, resulting in reductions in the ATP level and oxidative phosphorylation in pulmonary fibroblasts. In addition, we showed that butyrate (C4), a short chain fatty acid (SCFA), exhibits potent antifibrotic activity by inhibiting expression of fibrosis markers. Butyrate treatment inhibited mitochondrial elongation in TGF-beta 1-treated lung fibroblasts and increased the mitochondrial membrane potential (MMP). Consistent with the mitochondrial observations, butyrate significantly increased ADP, ATP, NADH, and NADH/NAD levels in TGF-beta 1-treated pulmonary fibroblasts. Collectively, our findings indicate that TGF-beta 1 induces changes in mitochondrial dynamics and energy metabolism during myofibroblast differentiation, and that these changes can be modulated by butyrate, which enhances mitochondrial function.