Upon activation, hepatic stellate cells (HSCs) undergo a pronounced phenotypic change that involves increased substrate availability to provide energy and building blocks. Activated HSCs obtain their energy through increased glycolysis, tricarboxylic acid (TCA) cycle activity, and mobilization of stored lipids that feed into beta oxidation, and nuclear translocation of pyruvate kinase M2 (PKM2) regulates metabolic gene expression. Glutamine represents an alternative source and enters the cell through alanine/serine/cysteine/threonine transporter 1 (ASCT1) before being metabolized to glutamate and α-ketoglutarate to feed into the TCA cycle. Furthermore, HSCs upregulate autophagic pathways to generate energy from cell organelles, including retinol-storing lipid droplets. Activated HSCs are abundant in free cholesterol, partly taken up through low-density lipoprotein receptor-related protein 5 (LRP5) interacting with proprotein convertase subtilisin/kexin type 9 (PCSK9), and cholesterol promotes expression of Toll-like receptor 4 (TLR4) and sensitizes HSCs to transforming growth factor beta (TGF-β) signaling. In addition, increased abundance of unfolded proteins and TGF-β signaling elicits an endoplasmic reticulum (ER) stress response through inositol-requiring enzyme 1 alpha (IRE1α), which upregulates fibrogenic gene expression through apoptosis-signal-regulating kinase 1 (ASK1)/c-Jun N-terminal kinase (JNK) signaling. In a self-perpetuating cycle, TGF-β signaling induces NADPH oxidase activity to produce H2O2, which supports fibrogenic gene expression and enables activation and release of extracellular latent TGF-β. Like macrophages, HSC activation is characterized by reduced nuclear receptor signaling (e.g. LXR, FXR, or THRα), although peroxisome proliferator-activated receptor β/δ is upregulated in activated HSCs and promotes their proliferation. ACAT1, acetyl-CoA acetyltransferase; DNL,de novolipogenesis; FXR, farnesoid X receptor; GLUT, glucose transporter; LXR, liver X receptor; LDL, low-density lipoprotein; SREBP-1c, sterol regulatory-element-binding protein 1; THR, thyroid hormone receptor. Created withBioRender.com.
