The hedgehog pathway in nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of obesity-associated liver diseases and it has become the major cause of cirrhosis in the Western world. The high prevalence of NAFLD-associated advanced liver disease reflects both the high prevalence of obesity-related fatty liver (hepatic steatosis) and the lack of specific treatments to prevent hepatic steatosis from progressing to more serious forms of liver damage, including nonalcoholic steatohepatitis (NASH), cirrhosis, and primary liver cancer. The pathogenesis of NAFLD is complex, and not fully understood. However, compelling evidence demonstrates that dysregulation of the hedgehog (Hh) pathway is involved in both the pathogenesis of hepatic steatosis and the progression from hepatic steatosis to more serious forms of liver damage. Inhibiting hedgehog signaling enhances hepatic steatosis, a condition which seldom results in liver-related morbidity or mortality. In contrast, excessive Hh pathway activation promotes development of NASH, cirrhosis, and primary liver cancer, the major causes of liver-related deaths. Thus, suppressing excessive Hh pathway activity is a potential approach to prevent progressive liver damage in NAFLD. Various pharmacologic agents that inhibit Hh signaling are available and approved for cancer therapeutics; more are being developed to optimize the benefits and minimize the risks of inhibiting this pathway. In this review we will describe the Hh pathway, summarize the evidence for its role in NAFLD evolution, and discuss the potential role for Hh pathway inhibitors as therapies to prevent NASH, cirrhosis and liver cancer.

Keywords: Nonalcoholic fatty liver disease; hedgehog; treatment; wound-healing response.

Figure 1. The hedgehog pathway

A. In the absence of the hedgehog (Hh) ligand, patch (Ptch) constitutively inhibits smoothened (Smo). This prevents the dissociation of the transcription factor Gli with its inhibitor Sufu, and allows Gli sequential phosphorylation by protein kinase A (PKA), casein kinase-1 (CK1) and glycogen synthase kinase-3 (GSK). Phosphorylated Gli is ubiquitinated through the action of transducin repeat containing protein (β-TrCP), which targets Gli to proteasomal degradation. The net result is the repressor form of Gli (Gli-R), which inhibits transcription of Gli-target genes. B. In the presence of Hh ligand, the Hh-Ptch complex is internalized and degraded. This removes the inhibitory effect of Ptch on Smo, and allows Smo entry into the primary cilium (PC). To become activated Smo is then phosphorylated through the action of CK1 and G-protein-couples receptor kinase-2 (GRK2). This allows the entry of the complex Sufu-Gli into the PC. At the tip of the PC, Sufu dissociates from Gli. Gli then returns to the cytoplasm where it undergoes partial degradation in the proteasome in an activated form. Activated Gli enters the nucleus, where it mediates transcription of Gli-target genes.

Figure 2

Pharmacological targeting of the hedgehog pathway.