A missense variant in human perilipin 2 (PLIN2 Ser251Pro) reduces hepatic steatosis in mice
Eleonora Scorletti,
Yedidya Saiman,
Sookyoung Jeon,
Carolin V. Schneider,
Delfin G. Buyco,
Chelsea Lin,
Blanca E. Himes,
Clementina A. Mesaros,
Marijana Vujkovic,
Kate Townsend Creasy,
Emma E. Furth,
Jeffrey T. Billheimer,
Nicholas J. Hand,
David E. Kaplan,
Kyong-Mi Chang,
Philip S. Tsao,
Julie A. Lynch,
Joseph L. Dempsey,
Julia Harkin,
Susovon Bayen,
Donna Conlon,
Marie Guerraty,
Michael C. Phillips,
Daniel J. Rader,
Rotonya M. Carr
Affiliations
Eleonora Scorletti
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Corresponding author. Address: Perelman School of Medicine at The University of Pennsylvania, Division of Translational Medicine and Human Genetics, Smilow Center for Translational Research, Room 11-130-3, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA
Yedidya Saiman
Department of Hepatology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
Sookyoung Jeon
Department of Food Science and Nutrition, Hallym University, Chuncheon, Gangwon-do, Republic of Korea
Carolin V. Schneider
Department of Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
Delfin G. Buyco
Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
Chelsea Lin
School of Medicine, Oregon Health & Science University, Portland, OR, USA
Blanca E. Himes
Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Clementina A. Mesaros
Department of Systems Pharmacology and Translational Therapeutics (SPATT) University of Pennsylvania, Philadelphia, PA, USA
Marijana Vujkovic
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Kate Townsend Creasy
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Emma E. Furth
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Jeffrey T. Billheimer
Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Nicholas J. Hand
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
David E. Kaplan
Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Kyong-Mi Chang
Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Philip S. Tsao
Precision Medicine, VA Palo Alto Health Care System, Palo Alto, CA, USA
Julie A. Lynch
VA Informatics & Computing Infrastructure, VA Salt Lake City Utah & University of Utah, School of Medicine, Salt Lake City, UT, USA
Joseph L. Dempsey
Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA
Julia Harkin
Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA
Susovon Bayen
Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA
Donna Conlon
Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania, PA, USA
Marie Guerraty
Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania, PA, USA
Michael C. Phillips
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Daniel J. Rader
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Rotonya M. Carr
Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA
Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is characterised by the accumulation of lipid droplets (LDs) within hepatocytes. Perilipin 2 (PLIN2) is the most abundant protein in hepatic LDs and its expression correlates with intracellular lipid accumulation. A recently discovered PLIN2 coding variant, Ser251Pro (rs35568725), was found to promote the accumulation of small LDs in embryonic kidney cells. In this study, we investigate the role of PLIN2-Ser251Pro (PLIN2-Pro251) on hepatic LD metabolism in vivo and research the metabolic phenotypes associated with this variant in humans. Methods: For our animal model, we used Plin2 knockout mice in which we expressed either human PLIN2-Pro251 (Pro251 mice) or wild-type human PLIN2-Ser251 (Ser251 mice) in a hepatocyte-specific manner. We fed both cohorts a lipogenic high-fat, high-cholesterol, high-fructose diet for 12 weeks. Results: Pro251 mice were associated with reduced liver triglycerides (TGs) and had lower mRNA expression of fatty acid synthase and diacylglycerol O-acyltransferase-2 compared with Ser251 mice. Moreover, Pro251 mice had a reduction of polyunsaturated fatty acids-TGs and reduced expression of epoxygenase genes. For our human study, we analysed the Penn Medicine BioBank, the Million Veteran Program, and UK Biobank. Across these databases, the minor allele frequency of PLIN2-Pro251 was approximately 5%. There was no association with the clinical diagnosis of NAFLD, however, there was a trend toward reduced liver fat in PLIN2-Pro251 carriers by MRI-spectroscopy in UK Biobank subjects. Conclusions: In mice lacking endogenous Plin2, expression of human PLIN2-Pro251 attenuated high-fat, high-fructose, high-cholesterol, diet-induced hepatic steatosis compared with human wild-type PLIN2-Ser251. Moreover, Pro251 mice had lower polyunsaturated fatty acids-TGs and epoxygenase genes expression, suggesting less liver oxidative stress. In humans, PLIN2-Pro251 is not associated with NAFLD. Impact and Implications: Lipid droplet accumulation in hepatocytes is the distinctive characteristic of non-alcoholic fatty liver disease. Perilipin 2 (PLIN2) is the most abundant protein in hepatic lipid droplets; however, little is known on the role of a specific polymorphism PLIN2-Pro251 on hepatic lipid droplet metabolism. PLIN2-Pro251 attenuates liver triglycerides accumulation after a high-fat-high-glucose-diet. PLIN2-Pro251 may be a novel lipid droplet protein target for the treatment of liver steatosis.
