Role of Hedgehog Signaling Pathway in NASH

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease in the Western world. Although only a minority of patients will ultimately develop end-stage liver disease, it is not yet possible to efficiently predict who will progress and, most importantly, effective treatments are still unavailable. Better understanding of the pathophysiology of this disease is necessary to improve the clinical management of NAFLD patients. Epidemiological data indicate that NAFLD prognosis is determined by an individual’s response to lipotoxic injury, rather than either the severity of exposure to lipotoxins, or the intensity of liver injury. The liver responds to injury with a synchronized wound-healing response. When this response is abnormal, it leads to pathological scarring, resulting in progressive fibrosis and cirrhosis, rather than repair. The hedgehog pathway is a crucial player in the wound-healing response. In this review, we summarize the pre-clinical and clinical evidence, which demonstrate the role of hedgehog pathway dysregulation in NAFLD pathogenesis, and the preliminary data that place the hedgehog pathway as a potential target for the treatment of this disease.

Signaling in Simple Steatosis and Non-alcoholic Steatohepatitis Cirrhosis: TGF-β1, YAP/TAZ, and Hedgehog Pathway Activity

“…These results are consistent with the finding of a previous study indicating that individuals with a mutated Smo gene were resistant to the progress of NAFLD (17). It is noteworthy that the exposure of normal hepatocytes with saturated fatty acids and lysophospholipids results in an increased expression of HH signaling pathway ligands (11). Therefore, there is a little chance that the expression of HH ligand in individuals with steatosis would be reduced due to exposure to lipid accumulation.…”

“…These hepatocytes are important sources of HH ligands (10) since the high amounts of HH pathway ligands is observed in human and animal NASH specimens. In addition, there is a direct relationship between the severity of liver disease and the activity of the HH pathway in the NAFLD from the NASH phase (11). Further investigations indicated that the expression of HH ligands in the liver tissue of patients with NASH cirrhosis was significantly higher than their expression in the liver tissue with SS (9).…”

“…Additionally, the HH pathway involves in differentiating hepatic stellate cells (HSCs) into myofibroblasts (11). Similarly, SHH is one of the important ligands of the HH signaling pathway, which is synthesized and secreted in adults mainly by damaged hepatocytes instead of the normal hepatocytes.…”

Nocturnal Hypoxia Activation of the Hedgehog Signaling Pathway Affects Pediatric Nonalcoholic Fatty Liver Disease Severity

“…There is increasing evidence supporting a role for dysregulation of the hedgehog (Hh) pathway in the pathogenesis of both adult and pediatric NAFLD . Hh, a morphogenic signaling pathway, controls organogenesis during organ development and is usually quiescent in adolescents and adults.…”

“…Although typically silent, Hh may be reactivated during injury that stimulates Hh ligand production. In the liver injury incited in both adult and pediatric NAFLD, activation of the Hh pathway is a dominant mechanism by which fibro‐inflammatory repair occurs …”