Reply:

Abstract

Reply: Balsano et al. studied Huh7.5 cells to evaluate the effects of Hedgehog (Hh) signaling on lipotoxicity. They concluded that Hh pathway inhibitors might be harmful in nonalcoholic fatty liver disease (NAFLD) because inhibiting Hh signaling in the malignant hepatocytes increased lipid accumulation. It is difficult to apply findings in cultured cancer cells to advance understanding of metabolism in nonmalignant hepatocytes because metabolism is fundamentally different in malignant and nonmalignant cells. Compared to benign hepatocytes, for example, malignant hepatocytes rely much more heavily on glycolysis (the Warburg effect).1 More important, nonmalignant hepatocytes are not Hh-responsive. Thus, hepatocytes in NAFLD livers would not be expected to respond directly to treatment with an Hh inhibitor. Rather, mature hepatocytes produce Hh ligands when injured. These hepatocyte-derived Hh ligands, in turn, initiate Hh signaling in neighboring stromal and progenitor cells. It is the Hh signaling in those nonhepatocyte cell types that drives hepatic fibrogenesis, recruitment of inflammatory cells, vascular remodeling, and progenitor accumulation.2 Thus, the desired “targets” for Hh inhibitors in NAFLD are nonparenchymal cells that participate in fibrogenic repair, not the hepatocytes per se. Finally, because Hh signaling inhibits lipogenesis in Hh-responsive cells,3 it is predictable that inhibiting Hh signaling would increase lipid accumulation in Huh7.5 cells. Triglyceride synthesis actually protects hepatocytes from toxic fatty acids.4 Thus, although not directly examined, Hh pathway inhibition might have improved Huh7.5 cell viability by enhancing lipogenesis. We hope that our response is helpful to the authors and thank them for their interest in our work.