1613-P: Sphingolipid Imbalance and Insulin Resistance in MAFLD-Related Sarcopenia

Introduction & Objective: Metabolic fatty liver disease (MAFLD) is closely related to dysregulation of systemic metabolism and insulin resistance (IR). Sarcopenia is often observed in individuals with MAFLD. Sphingolipids, known for their pivotal role in muscle cell regeneration and repair, have been suggested as key regulators in this context. This study aims to elucidate the potential connection between sphingolipid dysregulation in muscle and MAFLD.

Methods: Ten-week-old male mice with a C57BL/6J and 129S1/SvlmJ mixed background were subjected to either a WDSW (Western diet, Harlan, TD88137, and a high fructose-glucose solution, 23.1g/L D-fructose plus 18.9g/L D-glucose) or standard chow diet for 24 weeks, with free access to food and water. IPGTT and ITT tested were conducted at the end of the study. The sphingolipid profiles in the gastrocnemius muscle were determined using LC-MS/MS. The expression levels of sphingosine-1 phosphate receptors (S1PRs) were measured by qRT-PCR. The GEO data set (GSE73036) was downloaded and analyzed.

Result: Mice on the WDSW (MASH mice) exhibited significantly higher blood glucose levels and increased IR after 24 weeks of WDSW feeding. LC-MS/MS analysis indicated elevated levels of C18-Sphingomyelin (SM), C26-SM and C18:1 Dihydroceramide in the muscle of the WDSW group, while S1P levels were markedly reduced. The expression levels of S1PR1-3, the major types of S1PR in muscle, were also significantly decreased in MASH mice. Analysis of GSE73036 highlighted a strong correlation between IR and upregulation of S1P lyase (Spgl), an enzyme crucial for S1P degradation.

Conclusion: The findings of this study indicate a clear association between disrupted sphingolipid metabolism and IR in MASH mouse model. The observed increase in ceramide levels coupled with a decrease of S1P may contribute to sarcopenia associated with MAFLD.