2. Academic Validation
  3. Orosomucoid 2 maintains hepatic lipid homeostasis through suppression of de novo lipogenesis

Orosomucoid 2 maintains hepatic lipid homeostasis through suppression of de novo lipogenesis

  • Nat Metab. 2022 Sep;4(9):1185-1201. doi: 10.1038/s42255-022-00627-4.
Bing Zhou  # 1 2,  Yunchen Luo  # 3,  Nana Ji 4,  Cheng Hu 1,  Yan Lu 5 6
Affiliations

Affiliations

  • 1 Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
  • 2 Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai, China.
  • 3 Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
  • 4 Department of Endocrinology and Metabolism, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, China.
  • 5 Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai, China. rjluyan@126.com.
  • 6 Institute of Metabolism and Regenerative Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. rjluyan@126.com.
  • # Contributed equally.
PMID: 36050503 DOI: 10.1038/s42255-022-00627-4
Abstract

Non-alcoholic fatty liver disease (NAFLD) is caused by imbalance in lipid metabolism. In this study, we show that the hepatokine orosomucoid (ORM) 2 is a key regulator of de novo lipogenesis in the liver. Hepatic and plasma ORM2 levels are markedly decreased in obese murine models and patients with NAFLD. Through multiple loss- and gain-of function studies, we demonstrate that ORM2 is essential to maintain hepatic and systemic lipid homeostasis. At the mechanistic level, ORM2 binds to inositol 1, 4, 5-trisphosphate receptor type 2 to activate AMP-activated protein kinase signaling, thereby inhibiting sterol regulatory element binding protein 1c-mediated lipogenic gene program. Notably, intraperitoneal injections of recombinant ORM2 protein or stabilized ORM2-FC fusion protein markedly improved liver steatosis, steatohepatitis and atherosclerosis in preclinical mouse models, without adverse effects on body weight or food intake. Thus, these findings suggest that ORM2 may serve as a potential target for therapeutic intervention in NAFLD, non-alcoholic steatohepatitis and related lipid disorders.

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