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Kidney Week

ASN / Education & Meetings / Kidney Week /
Abstract: TH-PO438

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

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Torres, Jacob A., University of California Santa Barbara, Santa Barbara, California, United States
  • Aceves, Brina A., University of California Santa Barbara, Santa Barbara, California, United States
  • Messing, Melina, University of California Santa Barbara, Santa Barbara, California, United States
  • Holznecht, Nickolas J., University of California Santa Barbara, Santa Barbara, California, United States
  • Krishnan, Shreya, University of California Santa Barbara, Santa Barbara, California, United States
  • Razavi, Roxanna, University of California Santa Barbara, Santa Barbara, California, United States
  • Seligson, Anna Gabrielle, University of California Santa Barbara, Santa Barbara, California, United States
  • Weimbs, Thomas, University of California Santa Barbara, Santa Barbara, California, United States
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