Investigating the impact of abnormal lipid metabolism on mouse intervertebral disc

Project Summary/Abstract Hyperlipidemia, i.e. elevated serum lipids, has been identified as a risk factor for intervertebral disc (IVD) degeneration (IDD), but the underlying mechanism remains elusive. Epidemiologic studies have suggested mechanisms underlying hyperlipidemia and IDD other than obesity-induced mechanical stress, suggesting that elevated lipids may directly affect metabolic homeostasis in the IVD. However, oxygen demanding lipid metabolism has been considered minimal in hypoxic IVD, which has impeded investigation of this possibility thus far. Our preliminary data have uncovered an active lipid metabolism in mouse IVDs: they take up systemic lipids, undergo fatty acid oxidation (FAO) and store them in lipid droplets (LD). Furthermore, when lipid metabolism is disrupted by blocking FAO in a genetic mouse model or by lipid overload in a high-fat diet (HFD)-induced hyperlipidemia model, we observed significant lipid accumulation in nucleus pulposus (NP) cells. Histological evaluation revealed that in addition to abnormal lipid accumulation, there was a significant decrease in disc height and proteoglycan content in the NP in the HFD model. Biomechanical tests revealed a compromised mechanical strength of the IVDs from HFD-fed mice. In humans, the primary functional role of the IVD is to provide mechanical support to the spine. Reductions in proteoglycan content, disc height, and mechanical strength are early signs of IDD and can lead to severe IDD later in life. To investigate whether the early IDD changes caused by abnormal lipid metabolism can progress to severe IDD in the mouse models whose IVDs are not weight-bearing, we aim to comprehensively assess the mechanical properties of the intervertebral disc using an in vivo spinal instability-induced IDD mouse model in addition to the ex vivo testing system. In addition, we will establish a spatial lipidomics approach (Mass Spectrometry Imaging) and single- cell RNA sequencing in this training program to study metabolic changes and cellular responses to abnormal lipid metabolism in mouse models. We will also evaluate back pain-like behaviors in these animal models. The results of this project will reveal a novel mechanistic link between hyperlipidemia and IDD and lay the foundation for future studies exploring diagnostic/prophylactic/therapeutic approaches for lipid-related spine diseases.