Orosomucoid (ORM) is an important hepatokine that regulates metabolism. Previous report showed that isoform ORM2 but not ORM1 could downregulate lipogenic genes and ameliorate hepatic steatosis in obese mice, thereby categorizing ORM2 as a promising candidate for therapeutic intervention in nonalcoholic fatty liver disease (NAFLD). However, our previous studies found that mice lacking ORM1 gradually developed an obese phenotype with severe hepatic steatosis at the age of 24 weeks. Consequently, it remains imperative to further investigate the precise role of ORM1 in the context of NAFLD. The current study aims to assess the function and therapeutic prospects of ORM1 in NAFLD models induced by a high-fat diet (HFD) or a methionine- and choline-deficient diet (MCD), employing a series of loss- and gain-of-function experiments. The results showed that liver ORM levels elevated in fat NAFLD models but decreased in lean NAFLD models. Orm1-deficient mice fed either on HFD or MCD had significantly higher NAFLD activity score with more severe steatosis and ballooning, showing an aggravated NAFLD progression. However, liver-specific Orm1 overexpression in mice could not alleviate NAFLD when fed on HFD or MCD. These results suggest that systemic endogenous ORM1 is indispensable in protecting against the development of NAFLD
however, it may not serve as an effective localized therapeutic target for managing the disease.