Abstract
The massive production and activation of myofibroblasts (MFB) is key to the development of liver fibrosis. In many studies, it has been proven that hepatocytes are an important part of MFB, and can be transformed into MFB through epithelial-mesenchymal transition (EMT) during hepatic fibrogenesis. In our previous study, we confirmed that curcumin inhibited EMT procession and differentiation of hepatocytes into MFB. In addition, in previous studies, it has been shown that autophagy plays an important role in the regulation of cellular EMT procession. In the current study, we showed that curcumin inhibited TGF-β/Smad signaling transmission by activating autophagy, thereby inhibiting EMT. The mechanism of degradative polyubiquitylation of Smad2 and Smad3 is likely through inhibiting tetratricopeptide repeat domain 3 (TTC3) and by inducing ubiquitylation and proteasomal degradation of Smad ubiquitination regulatory factor 2 (SMURF2), which on account of the increase of autophagy in hepatocytes. Curcumin inhibits levels of reactive oxygen species (ROS) and oxidative stress in hepatocytes by activating PPAR-α, and regulates upstream signaling pathways of autophagy AMPK and PI3K/AKT/mTOR, leading to an increase of the autophagic flow in hepatocytes. In this study, we confirm that curcumin effectively reduced the occurrence of EMT in hepatocytes and inhibited production of the extracellular matrix (ECM) by activating autophagy, which provides a potential novel therapeutic strategy for hepatic fibrosis.
Highlights
Viral, alcoholic and non-alcoholic fatty liver disease is highly prevalent in China and around the world
These results indicated that curcumin alleviated pathological damage of hepatic fibrosis
Our findings showed that when compared with wild type mice, the phenomena of hepatic fibrosis were obvious in PPARα knockout mice, and the level of oxidative stress, the expression of Recombinant Nicotinamide Adenine Dinucleotide Phosphate Oxidase 1 (NOX1) increased, the effects induced by curcumin were weakened (Fig. 7C and D)
Summary
Alcoholic and non-alcoholic fatty liver disease is highly prevalent in China and around the world. 40% of patients will further develop liver fibrosis, cirrhosis, and even liver failure. Liver fibrosis is a common pathological procession in the development of various chronic liver diseases. Effective prevention and treatment of liver diseases are far from ideal, which is plaguing the medical community worldwide [1]. Liver fibrosis is due to excessive extracellular matrix (ECM) production and abnormal deposition of fibrous connective tissue in the liver. Pathological characteristics of liver fibrosis include proliferation and the deposition of collagen type I and collagen type III in the portal area and hepatic lobules. The massive production and activation of myofibroblasts (MFB) is key in the procession of liver fibrosis
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