The Effect of Prolyl Isomerase Pin1 on the Development of Metabolic Dysfunction-Associated Steatohepatitis and a New Treatment Strategy

Vollständiger Abstract

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Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by fatty liver, inflammation, and fibrosis, which eventually results in hepatocarcinoma. Recently, MASH therapeutics have been approved by the FDA; however, options remain limited, and the discovery of additional molecular targets is ongoing. The prolyl isomerase Pin1 regulates the function of phosphorylated substrates by converting the cis-trans form of proline. Pin1 interacts with specific substrates in each organ and controls lipid and energy metabolism through modulating the localization and stabilization of target proteins. Interestingly, a high-calorie diet upregulates Pin1 expression in the liver and adipocytes. It suppresses fatty acid oxidation, thermogenesis, and lipolysis by regulating PPARα, PRDM16, and adipose triglyceride lipase, which ultimately leads to steatosis. Beyond metabolic dysregulation, Pin1 is essential for activating hepatic stellate cells, which cause liver fibrosis. Pin1 conditional knockout mice exhibit resistance to high-calorie diet-induced MASH, which indicates a role for Pin1 in multiple organs as a central regulator linking metabolic dysfunction to liver inflammation and fibrosis. These results suggest that Pin1 inhibitors may be effective for MASH treatment. In this review, we discuss the roles of Pin1 in MASH development and as a potential therapy target.