(P09-005-25) Spinal Cord Injury-Induced MASH Occurs Independent of Hepatic Triglyceride Accumulation

Objectives: We reported that spinal cord injury (SCI) induces metabolic dysfunction-associated steatohepatitis (MASH). Remarkably, the phenotype of SCI-induced MASH occurs within days of injury despite rodents being lean and without excess energy intake, contrasting MASH most commonly occurring in association with obesity. Thus, the objective of this study was to identify neurogenic mechanisms responsible for SCI-mediated liver injury. We hypothesized that SCI shifts hepatic lipidomic and transcriptomics responses to promote MASH-associated liver injury.

Methods: Male C57B/6 mice (8-wk old) were fed a chow diet (13.6% fat) for 7 days prior to randomization to laminectomy or thoracic contusion injury (75kD). At 28 days post injury, MASH was assessed histologically and by direct measures of hepatic total lipid. Targeted transcriptomics and global unbiased lipidomics were evaluated by Nanostring and high-resolution mass spectrometry coupled with liquid chromatography, respectively. Data was analyzed by Wald- or t-test with FDR correction as appropriate.

Results: SCI induced MASH based on histological evidence of liver steatosis and macrophage (Kupffer cells) accumulation, and without between-group difference in body mass. SCI significantly shifted hepatic lipid classes, including decreased fatty acids, glycerolipids, and sphingolipids whereas glycerophospholipids (lysophosphatidylcholine (LPC); sphingomyelin (SM)) increased. Network analysis indicated that 8 of the top 10 reactions decreased by SCI were diacylglycerol esterification to triglyceride. Lipolysis of triglyceride to diacylglycerol were 6 of the top 10 reactions increased by SCI. In a separate cohort of mice, corroborating evidence from transcriptomics studies demonstrated that SCI downregulated lipogenic genes (Dgat1, Srebp1c) while upregulating cholesterol synthesis (Hmgcr) and decreasing cholesterol export (Abca1) genes.

Conclusions: SCI-induced neurogenic MASH is likely attributed to aberrant biosynthesis and sequestration of cholesterol potentially through LPC and SM mediated ER-stress and membrane remodeling, respectively, which can decrease Abca1 expression and function. This contrasts with triglyceride accumulation typical of obesity-associated MASH.

Funding Sources: NIH NIDDK and the OSU FFH.