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Article

An 8-Week Very Low-Calorie Ketogenic Diet (VLCKD) Alters the Landscape of Obese-Derived Small Extracellular Vesicles (sEVs), Redefining Hepatic Cell Phenotypes

by
Francesco Balestra
1,†,
Maria De Luca
1,†,
Giorgia Panzetta
1,
Nicoletta Depalo
2,3,
Federica Rizzi
2,3,
Rita Mastrogiacomo
4,
Sergio Coletta
5,
Grazia Serino
1,
Emanuele Piccinno
1,
Dolores Stabile
5,
Pasqua Letizia Pesole
5,
Valentina De Nunzio
6,
Giuliano Pinto
6,
Nicole Cerabino
7,
Martina Di Chito
7,
Maria Notarnicola
6,
Endrit Shahini
8,
Giovanni De Pergola
7,‡ and
Maria Principia Scavo
1,*,‡
1
Laboratory of Molecular Medicine, National Institute of Gastroenterology IRCCS “S. de Bellis”, Via Turi 27, Castellana Grotte, 70013 Bari, Italy
2
Institute for Chemical-Physical Processes, Italian National Research Council (IPCF)-CNR SS Bari, Via Orabona 4, 70125 Bari, Italy
3
National Interuniversity Consortium of Materials Science and Technology (INSTM), Bari Research Unit, Via Orabona 4, 70126 Bari, Italy
4
Department of Chemistry, University of Bari, Via Orabona 4, 70125 Bari, Italy
5
Core Facility Biobank, National Institute of Gastroenterology “S. de Bellis”, IRCCS Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy
6
Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology, “S. de Bellis”, Via Turi 27, Castellana Grotte, 70013 Bari, Italy
7
Center of Nutrition for the Research and the Care of Obesity and Metabolic Diseases, National Institute of Gastroenterology IRCCS “Saverio de Bellis”, Via Turi 27, Castellana Grotte, 70013 Bari, Italy
8
Gastroenterology Unit, National Institute of Gastroenterology IRCCS “S. de Bellis”, Via Turi 27, Castellana Grotte, 70013 Bari, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
These authors also contributed equally to this work.
Nutrients 2024, 16(23), 4189; https://doi.org/10.3390/nu16234189
Submission received: 4 November 2024 / Revised: 29 November 2024 / Accepted: 30 November 2024 / Published: 4 December 2024
(This article belongs to the Special Issue Dietary Advice and Guidance on Liver Metabolism)
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Abstract

Background. Very low-calorie ketogenic diets (VLCKD) are an effective weight-loss strategy for obese individuals, reducing risks of liver conditions such as non-alcoholic steatohepatitis and fibrosis. Small extracellular vesicles (sEVs) are implicated in liver fibrosis by influencing hepatic cell phenotypes and contributing to liver damage. This study investigates sEVs derived from serum of 60 obese adults categorized into low fibrosis risk (LR) and intermediate/high fibrosis risk (IHR) groups based on FibroScan elastography (FIB E scores, limit value 8 kPa) and all participants underwent an 8-week VLCKD intervention. Methods. The study examines the impact of these sEVs on fibrosis markers, inflammation, and autophagy in a hepatocyte cell line (HEPA-RG) using bioinformatics, RNA sequencing, lipidomics, RT-PCR, and Western blotting before (T0) and after (T1) VLCKD. Results. sEVs from LR patients post-VLCKD reduced fibrosis related gene expression (e.g., ACTA2) and enhanced proteins associated with regeneration and inflammation (e.g., HDAC6). Conversely, sEVs from IHR patients increased fibrosis and inflammation related gene expression (PIK3CB, AKT1, ACTA2) in hepatocytes, raising concerns about VLCKD suitability for IHR patients. IHR sEVs also decreased expression of HDAC10, HDAC6, HDAC3, MMP19, and MMP2, while increasing modulation of p-AKT, α-SMA, and VIM. Conclusion. These findings underscore the critical role of sEVs in regulating inflammation, remodeling, and hepatic stress responses, particularly in IHR patients, and suggest sEVs could complement instrumental evaluations like FibroScan in fibrosis assessment.
Keywords: VLCKD; fibrosis; liver disease; small extracellular vesicles; obesity VLCKD; fibrosis; liver disease; small extracellular vesicles; obesity

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MDPI and ACS Style

Balestra, F.; De Luca, M.; Panzetta, G.; Depalo, N.; Rizzi, F.; Mastrogiacomo, R.; Coletta, S.; Serino, G.; Piccinno, E.; Stabile, D.; et al. An 8-Week Very Low-Calorie Ketogenic Diet (VLCKD) Alters the Landscape of Obese-Derived Small Extracellular Vesicles (sEVs), Redefining Hepatic Cell Phenotypes. Nutrients 2024, 16, 4189. https://doi.org/10.3390/nu16234189

AMA Style

Balestra F, De Luca M, Panzetta G, Depalo N, Rizzi F, Mastrogiacomo R, Coletta S, Serino G, Piccinno E, Stabile D, et al. An 8-Week Very Low-Calorie Ketogenic Diet (VLCKD) Alters the Landscape of Obese-Derived Small Extracellular Vesicles (sEVs), Redefining Hepatic Cell Phenotypes. Nutrients. 2024; 16(23):4189. https://doi.org/10.3390/nu16234189

Chicago/Turabian Style

Balestra, Francesco, Maria De Luca, Giorgia Panzetta, Nicoletta Depalo, Federica Rizzi, Rita Mastrogiacomo, Sergio Coletta, Grazia Serino, Emanuele Piccinno, Dolores Stabile, and et al. 2024. "An 8-Week Very Low-Calorie Ketogenic Diet (VLCKD) Alters the Landscape of Obese-Derived Small Extracellular Vesicles (sEVs), Redefining Hepatic Cell Phenotypes" Nutrients 16, no. 23: 4189. https://doi.org/10.3390/nu16234189

APA Style

Balestra, F., De Luca, M., Panzetta, G., Depalo, N., Rizzi, F., Mastrogiacomo, R., Coletta, S., Serino, G., Piccinno, E., Stabile, D., Pesole, P. L., De Nunzio, V., Pinto, G., Cerabino, N., Di Chito, M., Notarnicola, M., Shahini, E., De Pergola, G., & Scavo, M. P. (2024). An 8-Week Very Low-Calorie Ketogenic Diet (VLCKD) Alters the Landscape of Obese-Derived Small Extracellular Vesicles (sEVs), Redefining Hepatic Cell Phenotypes. Nutrients, 16(23), 4189. https://doi.org/10.3390/nu16234189

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