Abstract
Pin1 is one of the three known prolyl-isomerase types and its hepatic expression level is markedly enhanced in the obese state. Pin1 plays critical roles in favoring the exacerbation of both lipid accumulation and fibrotic change accompanying inflammation. Indeed, Pin1-deficient mice are highly resistant to non-alcoholic steatohepatitis (NASH) development by either a high-fat diet or methionine–choline-deficient diet feeding. The processes of NASH development can basically be separated into lipid accumulation and subsequent fibrotic change with inflammation. In this review, we outline the molecular mechanisms by which increased Pin1 promotes both of these phases of NASH. The target proteins of Pin1 involved in lipid accumulation include insulin receptor substrate 1 (IRS-1), AMP-activated protein kinase (AMPK) and acetyl CoA carboxylase 1 (ACC1), while the p60 of the NF-kB complex and transforming growth factor β (TGF-β) pathway appear to be involved in the fibrotic process accelerated by Pin1. Interestingly, Pin1 deficiency does not cause abnormalities in liver size, appearance or function. Therefore, we consider the inhibition of increased Pin1 to be a promising approach to treating NASH and preventing hepatic fibrosis.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is characterized as hepatic steatosis that is not caused by factors such as significant alcohol consumption, chronic viral hepatitis and the side effects of medicines.In recent years, the number of NAFLD patients has been rising, showing trends similar to those of other diseases included in the metabolic syndrome category
transforming growth factor-β (TGF-β): transforming growth factor β. These findings indicate upregulated hepatic Pin1 expressions to be essential for non-alcoholic steatohepatitis (NASH) development, making contributions to both inflammation and lipid accumulation, with Pin1 deletion or inhibition markedly mitigating NASH symptoms according to the “multi-hit” theory
This study revealed that Pin1 promotes STAT3-mediated epithelial–mesenchymal transition, thereby inducing liver fibrosis
Summary
Non-alcoholic fatty liver disease (NAFLD) is characterized as hepatic steatosis that is not caused by factors such as significant alcohol consumption, chronic viral hepatitis and the side effects of medicines. Several clinical studies have suggested that dietary and exercise therapies for NASH/NAFLD improve biochemical indicators but do not ameliorate liver fibrosis [7,8]. Various drugs, such as antidiabetic agents, have been studied as potential treatments for NASH/NAFLD. The elucidation of the molecular mechanisms underlying NASH development is essential for developing novel treatments [9,10,11,12,13,14], which should be based on confirmed clinical evidence. The Pin expression level, as well as the phosphorylating activities mediated by serine/threonine-directed kinases, are important for the cis/trans isomerization at the proline residue of target proteins [19,20,21]. We consider Pin to be a key player in the development of NASH/NAFLD and discuss its roles in this review
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