Gut Microbiota Mediates SREBP-1c-Driven Hepatic Lipogenesis and Steatosis in Response to Zero-fat High-Sucrose Diet

Sucrose-rich diets promote hepatic de novo lipogenesis (DNL) and steatosis through interactions with the gut microbiota. However, the contribution of sugar-microbiota dynamics in the absence of dietary fat remains poorly understood. Here, we investigated the effects of a high-sucrose, zero-fat diet (ZFD) on hepatic steatosis and host metabolism in conventionally raised (CONVR) and germ-free (GF) mice. Our results show that the gut microbiota is essential for sucrose-induced DNL and hepatic steatosis. In CONVR ZFD-fed mice, hepatic fat was increased, accompanied by elevated expression of genes encoding DNL enzymes, higher levels of the rate-limiting DNL substrate malonyl-CoA, and upregulation of the master DNL regulator, SREBP-1c. Regardless of colonization status, ZFD induced the expression of fatty acid elongase and desaturase genes and increased hepatic monounsaturated fatty acids. Metabolomic analyses of portal vein plasma revealed microbiota-induced metabolites associated with hepatic steatosis in ZFD-fed mice. To further explore SREBP-1c's role, we used antisense oligonucleotides to knock down its hepatic expression in CONVR ZFD-fed mice. This intervention reduced hepatic steatosis and suppressed fatty acid synthase expression. In summary, our findings reveal that sucrose-microbiota interactions and SREBP-1c are critical drivers of DNL and hepatic steatosis in the absence of dietary fat, offering new insights into the complex interplay between diet, gut microbiota, and host metabolic regulation.