huINHBC/huINHBE Mouse

The inhibin βC subunit (INHBC) is a member of the transforming growth factor-β (TGF-β) superfamily. Its encoded precursor protein undergoes hydrolytic processing to form homodimers or heterodimeric activin complexes with βA/βB subunits, which are involved in inhibiting the activin A signaling pathway and regulating multiple physiological processes. INHBC is abundantly expressed in the liver and also participates in the regulation of hormone secretion in the reproductive system ^[1-2]. Studies have confirmed that circulating INHBC is associated with reduced subcutaneous fat, dyslipidemia, and increased risks of coronary artery disease (CAD) and non-alcoholic fatty liver disease (NAFLD). Meanwhile, obesity, hypertriglyceridemia, type 2 diabetes mellitus, and other conditions positively regulate plasma INHBC levels. Recombinant INHBC (Act-C) can inhibit lipolysis in adipocytes by activating the ALK7-SMAD2/3 signaling pathway, further clarifying its role in metabolic regulation ^[3].

The inhibin βE subunit (INHBE) is also a member of the TGF-β superfamily, with highly specific expression in hepatocytes. The precursor protein of INHBE generates the inhibin β subunit after proteolytic processing. This protein is associated with various cellular processes, including cell proliferation, apoptosis, immune response, and hormone secretion. During the development of obesity and diabetes, the expression of INHBE protein inhibits the proliferation and growth of relevant cells in the pancreas and liver. Research has found a positive correlation between INHBE expression in the liver and insulin resistance and body mass index (BMI), suggesting that INHBE may be a liver factor in altering systemic metabolic status under conditions of obesity-related insulin resistance ^[4]. The studies conducted by Alnylam Pharmaceuticals and the Regeneron Genetics Center (RGC), respectively, revealed the close relationship between INHBE and fat regulation. The research demonstrated that rare loss-of-function variants in INHBE may protect the liver from the impact of inflammation, abnormal blood lipids, and type 2 diabetes by promoting healthy fat storage. Patients carrying such mutations exhibit more normal fat distribution, significantly reduced abdominal fat, improved metabolic conditions, and a decreased risk of cardiovascular diseases and type 2 diabetes ^[5-7]. These findings suggest that INHBE is a liver-specific negative regulator of fat storage. Inhibiting the expression of INHBE genes and proteins may be a promising strategy for treating metabolic disorders associated with improper fat distribution and storage.

The huINHBC/huINHBE mouse is a dual-gene humanized model established via gene editing technology. In this model, the sequences from upstream of the mouse Inhbc exon 1 to the mouse Inhbe 3'UTR were replaced with the sequences from upstream of the human INHBC exon 1 to 3'UTR of the human INHBE. This model can be utilized for investigating the mechanisms and therapeutic approaches of fat distribution and storage, dyslipidemia, CAD, NAFLD, as well as for the development of INHBC/INHBE-targeted drugs.