Background and Aims: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome observed in chronic liver disease (CLD/cirrhosis). With an increasing prevalence of obesity-induced cirrhosis and evidence linking blood-derived lipids and brain lipid alterations to neurological impairment, we hypothesize that obese-induced brain lipid dysregulation increases the progression of HE in bile-duct ligated (BDL) rats. Aim: Study the impact of obesity on brain sphingolipids and the development of neurological impairment in a rat model of CLD and obesity. Method: CLD and HE model: 5-week BDL rats and Sham-controls, were used. Groups: Obese-BDL (O-BDL) and Obese-Sham (O-Sham) received high-fat diet (HFD) for 25-days pre-BDL surgery and then proceeded with high-carbohydrate diet (HCD) for 5 weeks post-BDL; Lean-BDL (L-BDL) and Lean-Sham (L-Sham) received regular-diet (RD) pre-BDL surgery and then HCD post-BDL. Body weight (BW), fat-mass, behavior, plasma liver markers and brain hippocampal sphingolipids were measured at 0 (pre-BDL), 3 and 5 weeks post-BDL. Results: Pre-BDL, HFD lead to increased BW and fat mass vs RD which was sustained with HCD in O-BDL vs L-BDL at 3 and 5 weeks. Ammonia, albumin, AST, ALT, ALP and bilirubin were impaired in O-BDL and L-BDL vs Shams at 3 and 5 weeks. High-density and low-density (LDL) lipoprotein levels were detected in pre-BDL rats which persisted in O-BDL and L-BDL vs controls at 3 and 5 weeks. LDL and total-cholesterol were higher in O-BDL vs L-BDL at 5 weeks. Short- and long-term (LTM) memory were impaired in both BDL groups at 5 weeks, whereas at 3 weeks, LTM impairment was found solely in O-BDL. Furthermore at 3 weeks, motor coordination was reduced in O-BDL, but not in L-BDL. At 5 weeks, motor coordination decreased in both BDL groups, with worse performance in O-BDL vs L-BDL. At 3 and 5 weeks, skill learning improved in L-Shams and L-BDL, but not in O-Shams and O-BDL. Muscle-strength was reduced in L-BDL but not in O-BDL vs Shams. Hippocampal sphingomyelin lipids were increased in O-BDL vs L-BDL rats at 0, 3 and 5 weeks, while ceramides were only reduced at 5 weeks. Conclusion: CLD-obesity rat model is characterized by increased fat mass and hyperlipidemia pre- and post-BDL. Neurological decline in O-BDL rats developed earlier and was more severe vs L-BDL rats. In addition, different neurological impairments developed in O-BDL vs L-BDL. Brain sphingolipid alteration in obese-cirrhotic rats may contribute to accelerate/worsen HE.
