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Background and Aims: Metabolic syndrome (MetS) is a pathologic condition characterized by abdominal obesity, insulin resistance, hypertension, and dyslipidemia. The prevalence of MetS parallels the rise of obesity rate reaching pandemic proportions due to the increased consumption of high-calories-high-fat-high-carbohydrates low-fibers diet associated with a sedentary lifestyle. MetS is associated with a plethora of comorbidities as non-alcoholic fatty liver disease (NAFLD). Noteworthy, NAFLD is considered the hepatic manifestation of MetS, and it can further progress to non-alcoholic steatohepatitis (NASH) that, in its turn, can evolve to cirrhosis and hepatocellular carcinoma (HCC). Despite the clinical relevance of NAFLD/NASH, however, effective therapy is still lacking. Lifestyle changes, including diet and physical activity, are so far the most effective interventions in NAFLD. Referring to nutritional approaches, however, there is not a definitive agreement concerning the dietary regimen to introduce into clinical practice. In this study, we investigated the capacity of a cholesterol-free ketogenic diet (KD) to improve pathological parameters associated with experimental MetS. Methods: MetS was induced in C57BL/6 mice by feeding with a cholesterol-enriched western diet (WD) up to 16 weeks followed by the switching to KD for further 8 weeks. WD and KD were chemical characterized through GC and SD-PAGE analysis. Results: KD administration in MetS mice significantly improved the liver pathological manifestations by lowering the gene expression of pro-inflammatory/fibrogenetic markers such as CCl2, IL-12, CD11b, OPN, Gal-3, TGF-β and α1-procollagen. Furthermore, KD feeding decreased the hepatic content of triglycerides and the hepatocellular damage, as testified by the reduction in ALT release. These observations were further supported by the histological analyses that revealed a significant amelioration in the extent of steatosis, necro-inflammation, and collagen fibers deposition, as confirmed by the Sirius-red staining in KD-fed mice. Interestingly, KD reduced the splenomegaly observed in WD-fed mice suggesting a reduction in chronic systemic inflammation. Finally, KD feeding ameliorated WD-induced muscle atrophy as confirmed by the recovery of the gastrocnemius mass. Microbiota analyses are ongoing. Conclusion: Altogether these results suggest that cholesterol-free ketogenic diet administration might represent a potential therapeutic strategy for MetS.

Cholesterol-Free Ketogenic Diet Administration Ameliorates Experimental Metabolic Syndrome