huPCSK9/huINHBE Mouse

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease primarily produced by the liver and also expressed in the intestine, heart, pancreas, renal interstitial cells, and neurons. The N-terminal domain of the PCSK9 protein is responsible for protein localization and stability, while the C-terminal domain mediates enzymatic activity ^[1]. PCSK9 is closely involved in the regulation of circulating cholesterol. Low-density lipoprotein receptor (LDLR) clears low-density lipoprotein cholesterol (LDL-C) from the blood. PCSK9 binds to and cleaves the intracellular domain of cell-surface LDLR, promoting its shedding from the plasma membrane and subsequent trafficking to lysosomes for degradation, thereby elevating plasma LDL-C levels. Overexpression of the PCSK9 gene or gain-of-function mutations reduce LDLR levels, leading to LDL-C accumulation, hypercholesterolemia, and increased risk of cardiovascular diseases such as atherosclerosis and coronary heart disease, as well as stroke and neurodegenerative diseases including Alzheimer’s disease (AD) ^[2].

Inhibin βE subunit (INHBE) is a member of the transforming growth factor-β (TGF-β) superfamily and is highly specifically expressed in hepatocytes. After proteolytic processing of the INHBE precursor, the inhibin β subunit is generated and participates in multiple cellular processes, including proliferation, apoptosis, immune responses, and hormone secretion. During the development of obesity and diabetes, INHBE protein expression can suppress the proliferation and growth of relevant cells in the pancreas and liver. Studies have shown that hepatic INHBE expression is positively correlated with insulin resistance and body mass index (BMI) in humans, suggesting that INHBE may act as a hepatic factor that alters systemic metabolic status under conditions of obesity-associated insulin resistance ^[3]. In addition, rare loss-of-function (LOF) mutations in INHBE may protect the liver from inflammation, dyslipidemia, and type 2 diabetes (T2D) by promoting healthy fat storage. Carriers of such mutations exhibit more normal fat distribution, markedly reduced abdominal fat, favorable metabolic profiles, and significantly lower risks of cardiovascular disease and type 2 diabetes (T2D) ^[4-6]. These findings indicate that INHBE is a liver-specific negative regulator of fat storage, and that inhibition of INHBE gene and protein expression may represent a potential therapeutic strategy for metabolic diseases associated with improper fat distribution and storage.

huPCSK9/huINHBE mice are dual-gene humanized models generated by crossing huPCSK9 mice (Catalog No.: C001617) with huINHBE mice (Catalog No.: C001533). These models can be used for screening, pharmacodynamic evaluation, safety assessment, and mechanism-of-action studies of dual-target drugs against PCSK9/INHBE, providing an ideal preclinical research platform for the development of innovative therapies for lipid metabolism disorder-related metabolic diseases, including hypercholesterolemia, atherosclerosis, obesity, and type 2 diabetes (T2D).