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Semin Liver Dis 2023; 43(04): 418-428
DOI: 10.1055/a-2187-3382
Review Article

Hedgehog Signaling: Implications in Liver Pathophysiology

Rajesh Kumar Dutta
1   Department of Medicine, Duke University, Durham, North Carolina
,
JiHye Jun
1   Department of Medicine, Duke University, Durham, North Carolina
,
Kuo Du
1   Department of Medicine, Duke University, Durham, North Carolina
,
Anna Mae Diehl
1   Department of Medicine, Duke University, Durham, North Carolina
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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 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 to maintain liver health.

Keywords

morphogenic - metabolic stress - lipotoxicity - senescence - secretome - accelerated aging


Publication History

Accepted Manuscript online:
06 October 2023

Article published online:
10 November 2023

© 2023. Thieme. All rights reserved.

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