Hedgehog Signaling: Implications in Liver Pathophysiology

Abstract

The purpose of this review is to summarize current knowledge about the role of the Hedgehog signaling pathway in liver homeostasis and disease. Hedgehog is a morphogenic signaling pathway that is active in development. In most healthy tissues, pathway activity is restricted to stem cell and/or stromal cell compartments, where it enables stem cell self-renewal and tissue homeostasis. Aberrant over-activation of Hedgehog signaling occurs in many cancers, including hepatocellular and cholangio- carcinoma. The pathway is also activated transiently in stromal cells of injured tissues and orchestrates normal wound healing responses, including inflammation, vascular remodeling and fibrogenesis. In liver, sustained Hedgehog signaling in stromal cells plays a major role in the pathogenesis of cirrhosis. Hedgehog signaling was thought to be silenced in healthy hepatocytes. However, recent studies show that targeted disruption of the pathway in hepatocytes dysregulates lipid, cholesterol, and bile acid metabolism and promotes hepatic lipotoxicity, insulin resistance and senescence. Hepatocytes that lack Hedgehog activity also produce a secretome that activates Hedgehog signaling in cholangiocytes and neighboring stromal cells to induce inflammatory and fibrogenic wound healing responses that drive progressive fibrosis. In conclusion, Hedgehog signaling must be precisely controlled in adult liver cells in order to maintain liver health.

A Decrease in the Activity of Inflammatory and Fibrogenic Pathways in Non-alcoholic Fatty Liver Disease as a Potential Defensive Strategy: A Mini-review

“…It has been shown that Hh pathway deficiency in hepatocytes dysregulates lipid metabolism and promotes hepatic lipotoxicity and metabolic consequences, including insulin resistance. Further, this condition induces inflammatory responses and fibrogenesis (10). In recent studies, it has been suggested that the Hippo signaling pathway is a player in NAFLD pathogenesis.…”