Available online 9 December 2023, 101851

High ORMDL3 overexpression in obese male but not female mice fed an obesogenic diet exacerbated adipocyte hypertrophy, insulin resistance, hepatic steatosis, liver fibrosis and inflammation, leading to earlier NASH development.

Mechanistically, ORMDL3 overexpression reduced levels of the bioactive sphingolipid metabolites S1P and ceramide only in obese female mice and antithetically, increased them in obese males and also robustly increased hepatic ER stress in obese male mice.

Obesogenic diet induces ORMDL expression in male mice but reduces it in females.

A novel role of ORMDL3 in sexual dimorphism that is important for NASH development.

Increased ORMDL3 expression may be a risk factor for the development of NASH in obese males and relevant to the greater incidence of NASH in men than in women.

The bioactive sphingolipid metabolites ceramide and sphingosine-1-phosphate (S1P) accumulate with overnutrition and have been implicated in non-alcoholic steatohepatitis (NASH) development. ORMDL3, a negative regulator of the rate-limiting step in ceramide biosynthesis, has been identified as an obesity-related gene. Therefore, we assessed the role of ORMDL3 in diet-induced obesity and development of NASH.

Globally overexpressing Ormdl3-Flag transgenic mice (ORMDL3TG) were fed a western high-fat, carbohydrate and cholesterol enriched diet, with high fructose-glucose drinking water. Physiological, biochemical and sphingolipidomic analyses were employed to measure the effect of ORMDL3 overexpression on NASH development.

ORMDL3TG male but not female mice fed a western high-fat diet and sugar water had exacerbated adipocyte hypertrophy together with increased severity of white adipose inflammation and fibrosis. Hepatic steatosis, dyslipidemia, impaired glucose homeostasis, hyperinsulinemia, and insulin resistance were significantly more severe only in obese ORMDL3TG male mice that accompanied dramatic liver fibrosis, inflammation, and formation of hepatic crown-like structures, which are unique features of human and murine NASH. Obesogenic diet induces ORMDL expression in male mice but reduces it in females. Mechanistically, overexpression of Ormdl3 lowered the levels of S1P and ceramides only in obese female mice and antithetically increased them in tissues of obese males. ORMDL3TG male mice exhibited a much greater induction of the UPR, propagating ER stress that contributed to their early development of NASH.

This study uncovered a previously unrecognized role for ORMDL3 in sexual dimorphism important for the development and progression of NASH.

NASH

hepatic steatosis

fibrosis

sphingolipids

ORMDL

adipose

© 2023 Published by Elsevier GmbH.