All transcripts were created with artificial intelligence software and modified with manual review by a third party. Although we make every effort to ensure accuracy with the manual review, some may contain computer-generated mistranslations resulting in inaccurate or nonsensical word combinations, or unintentional language. FASEB and the presenting speakers did not review the transcripts and are not responsible and will not be held liable for damages, financial or otherwise, that occur as a result of transcript inaccuracies.
Overexpression of OMRDL3 Confers Sexual Dimorphism in Diet-Induced Non-Alcoholic Steatohepatitis
Ryan D.R. Brown1, Christopher D. Green1, Cynthia Weigel1, Richard L Proia2, and Sarah Spiegel11Department of Biochemistry and Molecular Biology Virginia Commonwealth University School of Medicine, Richmond, VA
2Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD
Background and Aims: The bioactive sphingolipid metabolites, ceramide and sphingosine-1-phosphate (S1P), accumulate with overnutrition and play important roles in the development of murine and human non-alcoholic steatohepatitis (NASH). ORMDL3, a negative regulator of serine palmitoyltransferase, the rate-limiting step in ceramide biosynthesis, has been identified as an obesity-related gene that negatively correlates with body mass index. Therefore, we sought to assess the role of ORMDL3 in diet-induced obesity and the development of NASH.
Methods: Globally overexpressing Ormdl3 transgenic mice were fed a Western high-fat diet and sugar water for 18 weeks. Various metabolic parameters were measured prior to euthanasia that included intraperitoneal glucose tolerance, intraperitoneal insulin tolerance, metabolic chamber phenotyping and body composition analysis. Following euthanasia white adipose, brown adipose and liver were collected for biochemical analysis.
Results: Globally overexpressing Ormdl3 transgenic mice were fed a Western high-fat diet and sugar water. Male mice had greater weight gain on the diet than females; however, this sexual difference was not altered by Ormdl3 overexpression. Nevertheless, Ormdl3 transgenic male mice had worsened adipocyte hypertrophy accompanied by increased severity of white adipose inflammation and fibrosis. This adipose dysfunction in obese Ormdl3 transgenic mice led to abhorrent adipose-liver crosstalk and increased circulating cholesterol, phospholipids, and pro-inflammatory MCP1 only in obese male ORMDL3TG mice. Moreover, hepatic steatosis, dyslipidemia, impaired glucose homeostasis, hyperinsulinemia, and insulin resistance, were all significantly more severe only in obese Ormdl3 transgenic male mice. These traits were accompanied by dramatic liver fibrosis, inflammation, and the formation of hepatic crown-like structures, a unique histopathological feature of NASH in obese Ormdl3 transgenic male mice. Mechanistically, overexpression of Ormdl3 lowered levels of S1P and ceramides in white adipose tissues, and to a lesser extent in liver, only in obese female mice. Surprisingly, levels of these bioactive sphingolipids were antithetically increased in these tissues of obese Ormdl3 transgenic male mice, which led to sphingolipid toxicity-mediated induction of the unfolded protein response (UPR), propagating lipotoxic ER-stress that led to early development of NASH.
Conclusions: This study uncovered a previously unrecognized role of ORMDL3, a regulator of bioactive sphingolipids, in sexual dimorphism in mice important for the development and progression of NASH. Our findings suggest that high levels of ORMDL3 may be a risk factor for the development of NASH in obese males, and potentially relevant to how NASH disproportionately affects more males than females.
This work was supported by a grant from the National Institutes of Health (R01GM043880 to S.S).