Journal Article Epublish
PubMed: 40236713 DOI: 10.3389/fimmu.2025.1518687
Vegetal oil-based ketogenic diet improves inflammation and fibrosis in experimental metabolic dysfunction-associated steatohepatitis.
Front Immunol 16:1518687
Authors: Alessia Provera, Naresh Naik Ramavath, Laila Lavanya Gadipudi, Cristina Vecchio, Marina Caputo, Alessandro Antonioli, Sabrina Tini, Anteneh Nigussie Sheferaw, Simone Reano, Nicoletta Filigheddu, Marcello Manfredi, Elettra Barberis, Luca Cocolin, Ilario Ferrocino, Monica Locatelli, Massimiliano Caprio, Frank Tacke, Emanuele Albano, Flavia Prodam, Salvatore Sutti
Affiliations
- Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University of Piemonte Orientale, Novara, Italy.
- Unit of Endocrinology, University of Piemonte Orientale, Novara, Italy.
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.
- Department of Sciences and Technological Innovation, University of Piemonte Orientale, Alessandria, Italy.
- Department of Agricultural, Forestry and Food Science, University of Torino, Grugliasco, Italy.
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, Novara, Italy.
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy.
- Laboratory of Cardiovascular Endocrinology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele, Rome, Italy.
- Department of Hepatology & Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Abstract
Background and aims
Metabolic dysfunction-associated steatohepatitis (MASH) represents a growing cause of liver cirrhosis and hepatocellular carcinoma (HCC). However, effective therapy for MASH is still lacking. Despite recent studies suggest that ketosis might improve MASH evolution, the mechanisms involved have not been explored since common ketogenic diets cause severe steatohepatitis in mice. In this study, we have investigated the capacity of a new-formulated ketogenic diet (KD) containing vegetal fat in improving liver alterations associated with experimental MASH.
Methods
MASH was induced in C57BL/6 mice by feeding a cholesterol-enriched Western Diet (WD) for up to 16 weeks, followed by switching animals to KD for an additional eight weeks.
Results
We observed that KD administration greatly increased ketone body production and significantly reduced liver and body weights. Moreover, liver proteomic analysis and functional tests evidenced an improved glucose and lipid metabolism along with insulin resistance in KD-fed mice. These metabolic effects were associated with an amelioration in MASH-associated gut dysbiosis and with an improvement of hepatic steatosis, parenchymal injury and liver fibrosis. From the mechanistic point of view mice receiving KD showed a significant reduction in liver TREM2-positive monocyte-derived macrophages forming crown-like aggregates along with a lowering in the hepatic expression of pro-inflammatory/pro-fibrogenic markers such as CCL2, IL-12, CD11b, α1-procollagen, TGF-β1, osteopontin, and galectin-3. Consistently, experiments showed that β-hydroxybutyrate supplementation reduced TREM2 and galectin-3 expression by cultured Raw 264.7 macrophages.
Conclusions
Altogether, these results indicate that ketogenic diet based on vegetal fat effectively improves MASH metabolic derangements and steatohepatitis, and it might represent a potential therapeutic strategy in this disease.
MeSH
Ketone Bodies, Galectins, Fibrosis, Macrophages, Non-Alcoholic Fatty Liver Disease, Galectin 3, Liver, Diet, Immune System Diseases, Diet, Ketogenic, Therapeutics