UC Santa Barbara

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder characterized by the formation of numerous cysts in the kidneys, leading to significant renal complications. ADPKD arises from mutations in either the PKD1 or PKD2 genes, which encode polycystin-1 and polycystin-2, respectively. A common extrarenal manifestation of ADPKD is liver cysts, which can be characterized as Polycystic Liver Disease (PLD) when 10 or more cysts are present. Emerging studies suggest that metabolic interventions that induce ketosis, such as a ketogenic diet, may offer therapeutic potential in modulating renal disease progression. In this study, we investigated the effects of ketosis on liver cyst progression in a rodent model of ADPKD. Tamoxifen inducible Pkd1fl/fl C57BL6 mice were used to create a ADPKD model that exhibits a liver cyst phenotype, showing increased biliary cysts, liver volume, inflammation and fibrosis. With this established model we conducted a comprehensive evaluation of cyst burden and biomarkers of disease progression after treated PLD animals were placed on a ketogenic diet for 12 weeks. Our findings indicate that the ketogenic diet significantly reduced liver volume, macrophage recruitment, collagen deposition, and altered the composition of cyst size in PLD animals compared to controls. These results highlight the potential of a ketogenic metabolic therapy (KMT) in managing ADPKD and Polycystic Liver Disease (PLD).