Hedgehog Signaling In NAFLD

The liver regulates lipid and energy homeostasis. Both processes are disrupted in the metabolic syndrome (MetS). Thus, it is not surprising that the MetS associates with nonalcoholic fatty liver disease (NAFLD). Emerging evidence links the MetS with deregulated activity of the Hedgehog pathway. Hedgehog is a lipid‐regulated signal transduction pathway that orchestrates tissue construction by controlling cell proliferation, viability and differentiation. Hedgehog ligands are lipid modified on both the C‐terminus (by cholesterol) and N‐terminus (by palmitate and other fatty acids). Lipid modification of Hedgehog ligands controls local ligand bioavailability (i.e, autocrine, juxtacrine and paracrine signaling), as well as ligand association with circulating carriers (e.g., exosomes and lipoproteins) that enable Hedgehogs to act as hormones (endocrine signaling). Hedgehog responsive cells express the membrane spanning receptor, Patched (Ptc), and its co‐receptor Smoothened (Smo). Smo activity controls the accumulation of Hedgehog‐regulated transcription factors Glioma (Gli)1, Gli2, and Gli3. In the absence of Hedgehog ligands, Ptc represses Smo. This permits Gli proteins to be degraded and/or processed to transcriptional repressors. When Hedgehog ligands bind to Ptc, the repressive actions of Ptc on Smo are relieved and transcriptional activator forms of Glis accumulate. Certain proteins (e.g., cell adhesion molecule downregulated by oncogenes, COD, and brother of COD (BOC) enhance interaction of lipid‐modified Hedgehog ligands with Ptc to promote Smo activation. Other proteins that restrict Hedgehog release (e.g., Boi) are regulated by cholesterol. Smo activity is also influenced by lipids: oxysterol intermediates in the cholesterol/bile acid biosynthesis pathways directly activate Smo, while Smo is directly inhibited by endogenous cannabinoids carried in VLDL particles. Hedgehog pathway activity varies across the spectrum of NAFLD. Pathway activity is low in nonalcoholic fatty liver (NAFL, a benign condition), increases in nonalcoholic steatohepatitis (NASH, a more serious form of liver damage), and is highest in NASH‐related cirrhosis (where liver‐related morbidity and mortality are greatest). Lipotoxic hepatocytes produce Hedgehog ligands that act locally to activate Hedgehog signaling in neighboring stromal cells, which then generate Hedgehog ligands to amplify pathway activation. Hedgehog signaling orchestrates the hepatic wound healing response, stimulating accumulation of cell types that are involved in liver regeneration (e.g., immune cells, myofibroblasts, activated sinusoidal endothelial cells, and liver progenitors). Indeed, transient Hedgehog pathway activation is necessary for optimal liver regeneration. However, regeneration stalls at the fibrogenic stage of wound healing when Hedgehog signaling is excessive, and this causes progressive liver fibrosis that results in cirrhosis. Treatments that reduce hepatocyte lipotoxicity in NAFLD patients decrease Hedgehog ligands and reduce accumulation of inflammatory cells and myofibroblasts, suggesting that curbing Hedgehog might prevent fibrosis progression in NAFLD. Support or Funding Information R37 AA‐010154, RO1 DK‐077794, R56 DK‐106633, UO1‐DK‐061713