Hepatic glycogenesis antagonizes lipogenesis by blocking S1P via UDPG.

The identification of mechanisms to store glucose carbon in the form of glycogen rather than fat in hepatocytes has important implications for the prevention of nonalcoholic fatty liver disease (NAFLD) and other chronic metabolic diseases. In this work, we show that glycogenesis uses its intermediate metabolite uridine diphosphate glucose (UDPG) to antagonize lipogenesis, thus steering both mouse and human hepatocytes toward storing glucose carbon as glycogen. The underlying mechanism involves transport of UDPG to the Golgi apparatus, where it binds to site-1 protease (S1P) and inhibits S1P-mediated cleavage of sterol regulatory element-binding proteins (SREBPs), thereby inhibiting lipogenesis in hepatocytes. Consistent with this mechanism, UDPG administration is effective at treating NAFLD in a mouse model and human organoids. These findings indicate a potential opportunity to ameliorate disordered fat metabolism in the liver.

Nonlinear eco-evolutionary games with global environmental fluctuations and local environmental feedbacks.

Environmental changes play a critical role in determining the evolution of social dilemmas in many natural or social systems. Generally, the environmental changes include two prominent aspects: the global time-dependent fluctuations and the local strategy-dependent feedbacks. However, the impacts of these two types of environmental changes have only been studied separately, a complete picture of the environmental effects exerted by the combination of these two aspects remains unclear. Here we develop a theoretical framework that integrates group strategic behaviors with their general dynamic environments, where the global environmental fluctuations are associated with a nonlinear factor in public goods game and the local environmental feedbacks are described by the 'eco-evolutionary game'. We show how the coupled dynamics of local game-environment evolution differ in static and dynamic global environments. In particular, we find the emergence of cyclic evolution of group cooperation and local environment, which forms an interior irregular loop in the phase plane, depending on the relative changing speed of both global and local environments compared to the strategic change. Further, we observe that this cyclic evolution disappears and transforms into an interior stable equilibrium when the global environment is frequency-dependent. Our results provide important insights into how diverse evolutionary outcomes could emerge from the nonlinear interactions between strategies and the changing environments.