The liver occupies a central position in whole-body glucose and lipid homeostasis. When dietary fat intake increases, lipid deposition in the liver rises, creating fertile ground for insulin resistance and type 2 diabetes. Hepatic steatosis, marked by massive fat accumulation in the organ, is thereby associated with several features of the metabolic syndrome, including hyperlipidemia and insulin resistance. In this context, the present work establishes a novel role for the inorganic phosphate transporter PiT1 (encoded by SLC20A1) in the regulation of metabolism.
To dissect this function, the authors generated mice in which the Pit1 gene is specifically inactivated in hepatocytes. This targeted deletion significantly improves glucose tolerance and insulin sensitivity, enhances insulin signaling, and decreases hepatic lipogenesis. The experiments combined in vivo metabolic analyses (glucose, insulin, and pyruvate tolerance tests in mice fed a high-fat diet), indirect calorimetry measurements, and cellular approaches in mouse embryonic fibroblasts and HepG2 cells to explore the underlying molecular mechanisms.
Mechanistically, the team identified the enzyme USP7 as an interaction partner of PiT1. Under unstimulated conditions, USP7 associates with the IRS1 protein, a key relay in the insulin pathway, and stabilizes it; upon insulin stimulation, the USP7/IRS1 complex normally dissociates, allowing the ubiquitination of IRS1 and its subsequent degradation by the proteasome. Pit1 deletion inhibits this dissociation during insulin stimulation, thereby preventing IRS1 ubiquitination and degradation. This results in a delayed negative feedback loop of insulin and prolonged insulin signaling, with increased phosphorylation of the insulin receptor and AKT. The authors further provide several lines of evidence indicating that these metabolic effects are independent of the phosphate transport function of PiT1: expression of a transport-deficient mutant restores AKT signaling in knockout cells, and phosphate uptake remains comparable between wild-type and deficient cells.
Physiologically, mice deficient in hepatocyte PiT1 are protected against high-fat diet–induced obesity and diabetes. The authors emphasize that USP7 has already been extensively studied in the context of carcinogenesis and that an inhibitor is available. They conclude that PiT1 represents a potential therapeutic target in the setting of metabolic syndrome, obesity, and diabetes, and that a finer characterization of how PiT1 modulates the activity of its partners could guide the development of modulators of hepatic fat deposition.