huPCSK9/huINHBE Mouse
Product Name
huPCSK9/huINHBE Mouse
Product ID
C002095
Strain Name
C57BL/6NCya-Pcsk9tm1(hPCSK9)Inhbetm1(hINHBE)/Cya
Backgroud
C57BL/6NCya
Status
When using this mouse strain in a publication, please cite “huPCSK9/huINHBE Mouse (Catalog C002095) were purchased from Cyagen.”
Product Type
Age
Genotype
Sex
Quantity
Gene Name
PCSK9 & INHBE
Gene Alias
FH3, PC9, FHCL3, NARC1, LDLCQ1, NARC-1, HCHOLA3
NCBI ID
Chromosome
Chr 1 (Human), Chr 12 (Human)
MGI ID
Datasheet
Strain Description
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).
Reference
Melendez QM, Krishnaji ST, Wooten CJ, Lopez D. Hypercholesterolemia: The role of PCSK9. Arch Biochem Biophys. 2017 Jul 1;625-626:39-53.
Seidah NG, Awan Z, Chrétien M, Mbikay M. PCSK9: a key modulator of cardiovascular health. Circ Res. 2014 Mar 14;114(6):1022-36.
Sugiyama M, Kikuchi A, Misu H, Igawa H, Ashihara M, Kushima Y, Honda K, Suzuki Y, Kawabe Y, Kaneko S, Takamura T. Inhibin βE (INHBE) is a possible insulin resistance-associated hepatokine identified by comprehensive gene expression analysis in human liver biopsy samples. PLoS One. 2018 Mar 29;13(3):e0194798.
Akbari P, Sosina OA, Bovijn J, Landheer K, Nielsen JB, Kim M, Aykul S, De T, Haas ME, Hindy G, Lin N, Dinsmore IR, Luo JZ, Hectors S, Geraghty B, Germino M, Panagis L, Parasoglou P, Walls JR, Halasz G, Atwal GS; Regeneron Genetics Center; DiscovEHR Collaboration; Jones M, LeBlanc MG, Still CD, Carey DJ, Giontella A, Orho-Melander M, Berumen J, Kuri-Morales P, Alegre-Díaz J, Torres JM, Emberson JR, Collins R, Rader DJ, Zambrowicz B, Murphy AJ, Balasubramanian S, Overton JD, Reid JG, Shuldiner AR, Cantor M, Abecasis GR, Ferreira MAR, Sleeman MW, Gusarova V, Altarejos J, Harris C, Economides AN, Idone V, Karalis K, Della Gatta G, Mirshahi T, Yancopoulos GD, Melander O, Marchini J, Tapia-Conyer R, Locke AE, Baras A, Verweij N, Lotta LA. Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes. Nat Commun. 2022 Aug 23;13(1):4844.
Deaton AM, Dubey A, Ward LD, Dornbos P, Flannick J; AMP-T2D-GENES Consortium; Yee E, Ticau S, Noetzli L, Parker MM, Hoffing RA, Willis C, Plekan ME, Holleman AM, Hinkle G, Fitzgerald K, Vaishnaw AK, Nioi P. Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity. Nat Commun. 2022 Jul 27;13(1):4319.
Adam RC, Pryce DS, Lee JS, Zhao Y, Mintah IJ, Min S, Halasz G, Mastaitis J, Atwal GS, Aykul S, Idone V, Economides AN, Lotta LA, Murphy AJ, Yancopoulos GD, Sleeman MW, Gusarova V. Activin E-ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice. Proc Natl Acad Sci U S A. 2023 Aug 8;120(32):e2309967120.
Strain Strategy
The huPCSK9/huINHBE mouse is a dual-gene humanized model obtained by crossing the huPCSK9 mouse (Catalog No.: C001617) with the huINHBE mouse (Catalog No.: C001533).
Figure 1. Gene editing strategy of huPCSK9 mice. The mouse Pcsk9 gene sequence was replaced with the corresponding sequences in the human PCSK9 gene, including the UTR regions.
Figure 2. Gene editing strategy of huINHBE mice. The sequences from the start codon to 3'UTR of mouse Inhbe were replaced with the sequences from the start codon to 3'UTR of human INHBE.
Application Area
Screening, pharmacodynamic evaluation, safety assessment, and mechanism-of-action studies of dual-target drugs against PCSK9/INHBE;
Research on lipid metabolism disorder-related metabolic diseases, including hypercholesterolemia, atherosclerosis, obesity, and type 2 diabetes (T2D).
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