An 8-Week Very Low-Calorie Ketogenic Diet , Redefining Hepatic Cell Phenotypes

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 ph...

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Published in:Nutrients 2024-12, Vol.16 (23)
Main Authors: Balestra, Francesco, De Luca, Maria, Panzetta, Giorgia, Depalo, Nicoletta, Rizzi, Federica, Mastrogiacomo, Rita, Coletta, Sergio, Serino, Grazia, Piccinno, Emanuele, Stabile, Dolores, Pesole, Pasqua Letizia, De Nunzio, Valentina, Pinto, Giuliano, Cerabino, Nicole, Di Chito, Ma, Notarnicola, Maria, Shahini, Endrit, De Pergola, Giovanni, Scavo, Maria Principia
Format: Article
Language:English
Subjects:
Diet
Gene expression
Genes
Genetic aspects
Inflammation
Liver diseases
Phenotype
Proteins
RNA
RNA sequencing
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Summary: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.
ISSN:2072-6643
2072-6643
DOI:10.3390/nu16234189