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

Abstract

Non-alcoholic fatty liver disease (NAFLD) refers to the accumulation of fat in the liver tissue that is usually associated with metabolic disorders. Traditionally, the disease is regarded as a spectrum of pathological conditions ranging from simple steatosis (SS) to non-alcoholic steatohepatitis (NASH) and hepatic fibrosis with progression to cirrhosis. However, so far, there is no available explanation for the disease progression. Several signaling pathways such as transforming growth factor (TGF)-β, hedgehog (HH), and yes-associated protein 1 (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling are attributed to the NAFLD pathogenesis. TGF-β1 pathway component expression aligns with HH pathway ligands expression elevate in NASH cirrhosis while they decrease in SS. YAP and TAZ are two transcriptional co-activators from the Hippo signaling pathway. Similarly, the TAZ level (but not YAP1) is higher in NASH cirrhosis compared to SS. In addition, these three signaling pathways have little molecular similarity but their changes are totally similar in SS and NASH cirrhosis. The present review discusses the main changes in the expression of TGF-β, HH, and YAP/TAZ pathway components in SS and NASH cirrhosis. It is hoped that these data provide a better understanding of the mechanisms that underlie the pathophysiology of NAFLD.

Sonic Hedgehog Signaling, Lipids, and Metabolic Disorders

“…Experimental studies demonstrated that the HH pathway ligand is overexpressed in non-alcoholic steatohepatitis (NASH) specimens. Additionally, it has been reported that the severity of liver disease is directly related to the activity of the SHH pathway in non-alcoholic fatty liver disease (19). However, studies on the liver tissue of patients with simple steatosis revealed that the SHH signaling pathway was downregulated in simple steatosis as compared to NASH-related cirrhosis (20).…”