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Abstract Details
Atorvastatin favorably modulates a clinical hepatocellular carcinoma risk gene signature
Hepatol Commun. 2022 Sep;6(9):2581-2593. doi: 10.1002/hep4.1991. Epub 2022 Jun 16.
1Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston, Massachusetts, USA.
2Department of Gastroenterology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, South Korea.
3Department of Gastroenterology, Chaum Life Center, CHA University School of Medicine, Seoul, South Korea.
4Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
5Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
6Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
7Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
8Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.
9Pole Hepato-digestif, IHU, Strasbourg University Hospitals, Strasbourg, France.
Abstract
Lipophilic but not hydrophilic statins have been shown to be associated with reduced risk for hepatocellular carcinoma (HCC) in patients with chronic viral hepatitis. We investigated differential actions of lipophilic and hydrophilic statins and their ability to modulate a clinical prognostic liver signature (PLS) predicting HCC risk in patients with liver disease. Hepatitis C virus (HCV)-infected Huh7.5.1 cells, recently developed as a model to screen HCC chemopreventive agents, were treated with lipophilic statins (atorvastatin and simvastatin) and hydrophilic statins (rosuvastatin and pravastatin), and then analyzed by RNA sequencing and PLS. Lipophilic statins, particularly atorvastatin, more significantly suppressed the HCV-induced high-risk pattern of PLS and genes in YAP and AKT pathway implicated in fibrogenesis and carcinogenesis, compared with the hydrophilic statins. While atorvastatin inhibited YAP activation through the mevalonate pathway, the distinctive AKT inhibition of atorvastatin was mediated by stabilizing truncated retinoid X receptor alpha, which has been known to enhance AKT activation, representing a target for HCC chemoprevention. In addition, atorvastatin modulated the high-risk PLS in an in vitro model of nonalcoholic fatty liver disease (NAFLD). Conclusion: Atorvastatin distinctively inhibits YAP and AKT activation, which are biologically implicated in HCC development, and attenuates a high-risk PLS in an in vitro model of HCV infection and NAFLD. These findings suggest that atorvastatin is the most potent statin to reduce HCC risk in patients with viral and metabolic liver diseases.