The PNPLA3 variant I148M reveals protective effects toward hepatocellular carcinoma in mice via restoration of omega-3 polyunsaturated fats.

Autor: Patsenker E; Department of Gastroenterology and Hepatology, University of Zurich, Zurich, Switzerland. Electronic address: eleonora.patsenker@usz.ch., Thangapandi VR; Department of Gastroenterology and Hepatology, Universitätsklinikum Dresden, Dresden, Germany; Center for Regenerative Therapies, TU Dresden, Dresden, Germany., Knittelfelder O; Max Plank Institute of Molecular Cell Biology and Genetics, Dresden, Germany., Palladini A; Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany; German Center for Diabetes Research, Neuherberg, Germany., Hefti M; Department of Gastroenterology and Hepatology, University of Zurich, Zurich, Switzerland., Beil-Wagner J; Institute of Laboratory Animal Science, University of Zurich, Schlieren, Switzerland., Rogler G; Department of Gastroenterology and Hepatology, University of Zurich, Zurich, Switzerland., Buch T; Institute of Laboratory Animal Science, University of Zurich, Schlieren, Switzerland., Shevchenko A; Max Plank Institute of Molecular Cell Biology and Genetics, Dresden, Germany., Hampe J; Department of Gastroenterology and Hepatology, Universitätsklinikum Dresden, Dresden, Germany; Center for Regenerative Therapies, TU Dresden, Dresden, Germany., Stickel F; Department of Gastroenterology and Hepatology, University of Zurich, Zurich, Switzerland.
Jazyk: angličtina
Zdroj: The Journal of nutritional biochemistry [J Nutr Biochem] 2022 Oct; Vol. 108, pp. 109081. Date of Electronic Publication: 2022 Jun 10.
DOI: 10.1016/j.jnutbio.2022.109081
Abstrakt: Alcohol consumption and high caloric diet are leading causes of progressive fatty liver disease. Genetic variant rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3 rs738409 C>G) has been repeatedly described as one of the major risk loci for alcoholic liver cirrhosis (ALC) and hepatocellular carcinoma (HCC) in humans, however, the mechanism behind this association is incompletely understood. We generated mice carrying the rs738409 variant (PNPLA3 I148M) in order to detect genotype-phenotype relationships in mice upon chow and alcohol-high fat/high sugar diet (EtOH/WD). We could clearly demonstrate that the presence of rs738409 per se is sufficient to induce spontaneous development of steatosis after 1 year in mice on a chow diet, whereas in the setting of unhealthy diet feeding, PNPLA3 I148M did not affect hepatic inflammation or fibrosis, but induced a striking lipid remodeling, microvesicular steatosis and protected from HCC formation. Using shot gun lipidomics, we detected a striking restoration of reduced long chain-polyunsaturated fatty acids (LC-PUFA)-containing TGs, docosapentaenoic acid (C22:5 n3) and omega-3-derived eicosanoids (5-HEPE, 20-HEPE, 19,20-EDP, 21-HDHA) in PNPLA3 I148M mice upon EtOH/WD. At the molecular level, PNPLA3 I148M modulated enzymes for fatty acid and TG transport and metabolism. These findings suggest (dietary) lipids as an important and independent driver of hepatic tumorigenesis. Genetic variant in PNPLA3 exerted protective effects in mice, conflicting with findings in humans. Species-related differences in physiology and metabolism should be taken into account when modeling unhealthy human lifestyle, as genetic mouse models may not always allow for translation of insight gained in humans.
Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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