Hepatic Lipotoxicity, Metabolic Homeostasis and NAFLD Pathogenesis

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Modified Project Summary/Abstract Section Nonalcoholic fatty liver disease (NAFLD) afflicts one in three adults and poses a major public health threat and economic burden because it can cause cirrhosis and liver cancer. These poor outcomes mainly occur in patients with fatty livers who develop hepatocyte injury (lipotoxicity) and nonalcoholic steatohepatitis (NASH) but then mount maladaptive repair responses. Preventing and treating NAFLD-related cirrhosis and liver cancer has been limited by gaps in knowledge about mechanisms that control susceptibility to NASH, and that determine whether responses to repair NASH are effective or maladaptive. This project evaluates the general hypothesis that hepatocyte Hedgehog activity controls susceptibility to NASH (lipotoxicity) and NASH cirrhosis (maladaptive repair). Hedgehog is a morphogenic signaling pathway that orchestrates liver development in embryos. It was thought to be silenced in adult hepatocytes but emerging evidence suggests that it remains active in subpopulations of hepatocytes in adult livers. Because Smoothened (a critical component of the Hedgehog pathway) is directly regulated by lipids, we postulated that the Hedgehog pathway might be dysregulated in NAFLD. We selectively manipulated Smoothened in hepatocytes and applied state-of-the-art approaches, including single cell RNA seq analysis, to determine if/how Hedgehog signaling regulates hepatocyte metabolism. Remarkably, we found that inhibiting Hedgehog activity in hepatocytes was sufficient to induce NAFL and evoke many abnormalities that have been implicated in the pathogenesis of NASH. The current project evaluates a novel conceptual model for NAFLD pathogenesis that derives from our provocative new data showing that hepatocytes require Hedgehog pathway activity to protect themselves from lipotoxic stress caused by iron-catalyzed lipid peroxidation and evidence that loss of Hedgehog signaling in hepatocytes triggers compensatory responses, including over-production of Hedgehog ligands, that drive maladaptive repair responses in Hedgehog-responsive stromal cells. Successful completion of our Aims will broaden current paradigms about NAFLD pathogenesis and open new opportunities for future discovery to improve NAFLD diagnosis and treatment.