Excess fasting de novo lipogenesis in pericentral hepatocytes drives pericentral steatosis during insulin resistance, sustained by hyperinsulinemia via the IRS1-mTORC1 signaling axis.
Excess fasting de novo lipogenesis in pericentral hepatocytes, driven by the IRS1-mTORC1 signaling axis, promotes steatosis progression during selective hepatic insulin resistance.
Introduction and Objective: Type 2 diabetes (T2D) accompanied by metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by unsuppressed hepatic glucose production and elevated de novo lipogenesis (DNL)—a paradoxical combination known as selective hepatic insulin resistance. Accumulating evidence indicates that excessive hepatic DNL is a major contributor to MASLD pathogenesis; however, the mechanisms that drive lipogenesis within the insulin-resistant liver remain poorly defined. Methods: The liver has a repeated lobular organization, in which periportal (PP) hepatocytes and pericentral (PC) hepatocytes exert distinct metabolic functions. Using Cyp1a2CreER, Gls2CreER, and the tdTomato lineage tracer, we delete genes specifically in PC or PP hepatocytes of adult mice and permanently mark these deleted cells. We integrate this spatial targeting with in vivo stable isotope tracing and fluorescence-activated cell sorting (FACS) of hepatocytes to quantify zone-specific metabolism. Results: We found that DNL is higher in PP hepatocytes than in PC hepatocytes in healthy mice. In contrast, insulin-resistant MASLD patients and diet-induced obese mice consistently exhibit lipid accumulation predominantly in PC hepatocytes—a phenomenon termed pericentral steatosis. These observations suggest that spatial regulation of lipogenesis during insulin resistance differs fundamentally from physiological conditions. Here, we show that during insulin resistance, excess fasting DNL in PC hepatocytes drives pericentral steatosis in mice fed a GAN diet. Mechanistically, amino acid catabolism supplies carbon substrates for lipogenesis, while fasting hyperinsulinemia sustains activation of lipogenic gene expression through the IRS1-mTORC1 signaling axis specifically in PC hepatocytes. Conclusion: Together, these spatially coordinated metabolic and signaling mechanisms promote steatosis progression during selective hepatic insulin resistance in T2D. Disclosure R. Tao: None. Funding R01DK133388
Rongya Tao (Fri,) conducted a other in Type 2 diabetes with metabolic dysfunction-associated steatotic liver disease (MASLD). Insulin resistance and GAN diet vs. Healthy mice and physiological conditions was evaluated on De novo lipogenesis and lipid accumulation. Excess fasting de novo lipogenesis in pericentral hepatocytes drives pericentral steatosis during insulin resistance, sustained by hyperinsulinemia via the IRS1-mTORC1 signaling axis.