Figure 1.

A schematic model of metabolism, autophagy, and epigenetics in HSC-to-MFB transdifferentiation based on evolving research insights. In this model, quiescent HSC exposed to various stimuli transdifferentiate to activated HSC (MFB) and loose lipid droplets (LDs). Prior to or during transdifferentiation, transcription-level alterations modulate the expression of relevant metabolic, autophagy, and epigenetic mediators (?). Epigenetic modifiers (e.g., HDACs, DNMTs, MECP2, etc.) may determine, which transcriptional networks are switched on or off. In the transdifferentiated state, increased glycolysis, pentose phosphate pathway (PPP), and antioxidant system as well as loss of LDs could synergize to sustain energy production (Hernández-Gea et al., 2012) and provide the metabolite pool for extracellular matrix (ECM) and collagen synthesis (?). In the activated state, MFB may rely on nutrients from accelerated de novo metabolism, microenvironment, or autophagic breakdown of organelles to sustain their function in fibrosis and inflammation, e.g., cytokine production. Microenvironmental factors may signal the end of healing by (a) activating antifibrotic epigenetic modifiers, (b) attenuating transcriptional activators of metabolism and autophagy, or (c) by inducing self-destructive autophagy in MFB (?). LPS, lipopolysaccharides; ?, unknown mechanisms.