Inhibition of hedgehog signaling ameliorates hepatic inflammation in mice with nonalcoholic fatty liver disease

Abstract

Hedgehog (Hh)-signaling plays a critical role in liver development, regeneration, injury repair and carcinogenesis. Activation of Hh signaling has been observed in patients with nonalcoholic fatty liver diseases (NAFLD); however, the pathobiological function and regulatory mechanism of hepatic Hh signaling in the pathogenesis of NAFLD remain to be further defined. This study was designed to examine the effect and mechanism of hepatic Hh signaling in high fat diet (HFD)-induced NAFLD by using pharmacological Smoothened inhibitors (GDC-0449 and LED225) and by using liver specific Smo knockout (Smo LKO) mice. Administration of Smo inhibitors to HFD-fed wild type mice significantly reduced the numbers of activated macrophages and decreased the expression of pro-inflammatory cytokines (TNFα, IL-1β, MCP1 and IL-6) as assessed by F4/80 immunohistochemistry and qRT-PCR, respectively. The Smo inhibitors were noted to have variable effects on hepatic fat accumulation. We observed that liver specific deletion of Smo also reduced macrophage activation and inhibited pro-inflammatory cytokine expression, while it did not significantly alter fat accumulation in the liver. Mechanistically, we found that activation of Gli1 by Hh signaling in primary hepatocytes increased the production of osteopontin (OPN) which subsequently enhanced macrophage-mediated pro-inflammatory response via a paracrine signaling. Conclusions: Hepatocyte Hh signaling can promote liver inflammation through OPN-mediated macrophage activation; this mechanism importantly contributes to the progression of NAFLD.

Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis

“…Hepatocytes also express components of the hedgehog signaling cascade, e.g., plasma membrane receptor smoothened, and may represent an important target of hedgehog signaling during lipotoxicity (51). Activation of Gli1, a transcription factor mediating canonical hedgehog signaling, increased production of osteopontin by hepatocytes, which in turn promoted macrophage-associated proinflammatory response in a paracrine fashion (124). Finally, inhibition of hedgehog signaling by pharmacological inhibitors of smooth ened (vismodegib and erismodegib) or genetic deletion of smoothened in the liver parenchyma prevents liver injury, inflammation, and fibrosis in mouse models of NAFLD and NASH (51,124).…”

Developmental origins of NAFLD: a womb with a clue

“…Hedgehog signalling is inhibited in healthy liver but activated in disease; ballooned hepatocytes produce the Hedgehog ligand sonic hedgehog, which stimulates hepatic stellate cells and fibroblasts, initiating a profibrotic response 237 . Inhibiting or eliminating smoothened, a G proteincoupled receptor mediating signalling in the presence of sonic hedgehog ligand 238 , resulted in reduced macrophage activation and expression of proinflammatory genes in a mouse model 239 . Analysis of liver biopsies from patients with NASH enrolled in the PIVENS trial showed that response to treatment (vitamin E) was inversely associated with levels of sonic hedgehog 240 .…”

Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation

“…21 Likewise, liver-specific deletion of smoothened attenuates liver inflammation in high fat diet-fed mice. 22 Interestingly, in patients with NASH enrolled in the PIVENS trial, improvement in liver injury correlated with a decreased number of Shh-positive hepatocytes. On the other hand, a reduction of Shh-positive hepatocytes was not associated with improvement of fibrosis in these patients.…”