LB100 ameliorates nonalcoholic fatty liver disease via the AMPK/Sirt1 pathway
**Background:** Nonalcoholic fatty liver disease (NAFLD) is commonly associated with insulin resistance (IR). LB100, an inhibitor of serine/threonine protein phosphatase 2A (PP2A), has been linked to IR, but its direct impact on NAFLD remains underexplored.
**Aim:** This study aims to investigate the effects and underlying mechanisms of LB100 in NAFLD.
**Methods:** Male C57BL/6 mice were fed a high-fat diet (HFD) for 10 weeks, followed by intraperitoneal injections of either vehicle or LB100 three times a week for an additional 6 weeks. The L02 cell line was exposed to LB100 and free fatty acids (FFAs) for 24 hours. Histological analysis was conducted using hematoxylin and eosin and oil red O staining. Protein levels of Sirtuin 1 (Sirt1), total and phosphorylated AMP-activated protein kinase α (AMPKα), and lipogenesis and fatty acid oxidation proteins were assessed by Western blotting. mRNA levels were measured by qPCR. To clarify LB100’s mechanism in NAFLD, AMPK was pharmacologically inhibited.
**Results:** LB100 significantly reduced LB-100 obesity, hepatic lipid accumulation, and liver injury induced by the HFD in mice. It notably decreased the protein levels of acetyl-CoA carboxylase, sterol regulatory element-binding protein 1, and its lipogenesis targets (including stearoyl-CoA desaturase-1 and fatty acid synthase), while increasing proteins involved in fatty acid β-oxidation (such as PPARα, PGC-1α, carnitine palmitoyltransferase 1α, acyl-CoA oxidase 1, and uncoupling protein 2), as well as upstream regulators Sirt1 and AMPKα in the liver. In vitro, LB100 mitigated FFA-induced lipid accumulation in L02 cells through the AMPK/Sirt1 signaling pathway. Inhibition of AMPKα in L02 cells nullified LB100’s beneficial effects on lipid accumulation.
**Conclusion:** LB100, through PP2A inhibition, significantly reduces hepatic steatosis by modulating hepatic lipogenesis and fatty acid oxidation via the AMPK/Sirt1 pathway, positioning it as a potential therapeutic agent for NAFLD.