A Ketogenic Diet Alters Liver Cyst Progression in a Rodent Model of Polycystic Kidney Disease and Is Dependent on GPR109A

Background: Polycystic Liver Disease (PLD) often co-occurs alongside Autosomal Dominant Polycystic Kidney Disease (ADPKD), a genetic disorder characterized by the growth of numerous cysts in the kidneys. Our lab has demonstrated that a low-carbohydrate, high-fat ketogenic diet, can slow and partially reverse kidney cyst growth in animal models of PKD in a mechanism involving the ketone beta-hydroxybutyrate (BHB). Furthermore, clinical evidence has found that ketogenic dietary interventions appear to be safe, feasible, and potentially beneficial for ADPKD patients. However, the impact of a ketogenic diet on PLD remains unexplored. This study aims to investigate the effects of a ketogenic diet and the BHB receptor, GPR109A, on PLD using an orthologous rodent model of PKD to build on the existing knowledge of the beneficial effects of such a diet on kidney cyst progression in ADPKD. Methods: We utilized wild-type and Gpr109a-knockout mice with a tamoxifen-inducible Pkd1fl/fl:ROSA-Cre system. Mice were induced on postnatal day 28 through postnatal day 30. Three days post-induction, the mice were segregated into two groups for a twelve-week dietary intervention: one group was fed a low carbohydrate (~5% of total calories), high-fat (~80% total calories) ketogenic diet, while the other group was maintained on standard chow. Following this period, tissues were harvested and subjected to a comprehensive analysis to assess disease progression, including histological and immunohistochemical analysis. Results: Our study revealed a marked manifestation of hepatic cysts in the induced animals, as depicted by a significant increase in both the number and size of bile ducts, liver mass, and collagen deposition when compared to uninduced controls. Treatment with a ketogenic diet significantly reduced liver mass and fibrosis and was dependent on Gpr109a. Additionally, the localization of immune cells exhibited distinctly different patterns in treated versus untreated cystic animals. Conclusion: We find that a ketogenic diet significantly blunts the growth of the liver due to PLD and markedly decreases collagen deposition. These findings underscore the potential of ketogenic dietary interventions as a novel therapeutic strategy for PLD and the importance of the receptor GPR109A. Funding: NIDDK Support, Government Support – Non-U.S.