B6-hKLB Mice

Catalog Number: C001622
Strain Name: C57BL/6NCya-Klbem1(hKLB)/Cya
Genetic Background: C57BL/6NCya

 

Strain Description

The KLB gene encodes β-Klotho, a transmembrane protein that functions as an obligate co-receptor for fibroblast growth factor (FGF) receptors, specifically for the endocrine FGF ligands FGF19 and FGF21 [1]. Expressed across metabolic tissues, including adipose, liver, and pancreas, KLB is a critical regulator of FGF19 and FGF21 signaling, impacting glucose homeostasis, energy balance, and bile acid metabolism [1-3]. β-Klotho facilitates FGF19 and FGF21 signaling through direct interaction with FGF receptors [1]. KLB gene expression is observed across various tissues, encompassing metabolic, haematopoietic, foetal, and adult tissues [1]. Perturbations in KLB function and genetic variants have been implicated in a range of disorders, including hypogonadotropic hypogonadism, male infertility, obesity, non-alcoholic fatty liver disease, irritable bowel syndrome, and potentially certain malignancies [1-4]. Thus, KLB emerges as a pivotal gene in FGF signaling, exerting pleiotropic effects on metabolic physiology and disease [1-4].

The B6-hKLB mouse is a humanized model generated using gene editing technology by integrating the Chimeric cDNA and the 3'UTR of the mouse Klb gene into the mouse Klb gene locus. The mouse Klb endogenous extracellular domain (aa.1~994) was replaced with the human KLB domain (aa.1~996), and the murine transmembrane-cytoplasmic region (aa.995~1043) was remained. Homozygous B6-hKLB mice are viable and fertile. This model can be used for research on the pathological mechanisms and treatment methods of metabolic diseases such as obesity, diabetes, metabolic-associated steatohepatitis (MASH), inflammatory diseases, and potentially selected malignancies and the development of KLB-targeted drugs.

 

Strain Strategy


Figure 1. Gene editing strategy of B6-hKLB mice. The coding sequences of exon 1 plus partial intron 1 of mouse Klb were replaced with the “Kozak-Chimeric cDNA-3'UTR of mouse Klb-WPRE-BGH pA" cassette. The mouse Klb endogenous extracellular domain (aa.1~994) was replaced with the human KLB domain (aa.1~996), and the murine transmembrane-cytoplasmic region (aa.995~1043) was remained.

 

Application

  • KLB-targeted drug screening, development, and evaluation;
  • Research on the pathological mechanisms and therapeutic approaches of metabolic diseases such as obesity, diabetes, and metabolic-associated steatohepatitis (MASH);
  • Research on the pathological mechanisms and therapeutic approaches of inflammatory diseases and potentially selected malignancies.

 

References
[1]Aaldijk AS, Verzijl CRC, Jonker JW, Struik D. Biological and pharmacological functions of the FGF19- and FGF21-coreceptor beta klotho. Front Endocrinol (Lausanne). 2023 May 16;14:1150222.
[2]Lu W, Li X, Luo Y. FGF21 in obesity and cancer: New insights. Cancer Lett. 2021 Feb 28;499:5-13.
[3]Shao W, Jin T. Hepatic hormone FGF21 and its analogues in clinical trials. Chronic Dis Transl Med. 2022 Feb 23;8(1):19-25.
[4]G. Schumann, C. Liu,P. O’Reilly, H. Gao, P. Song, B. Xu, B. Ruggeri, N. Amin, T. Jia, S. Preis, M. Segura Lepe, S. Akira, C. Barbieri, S. Baumeister, S. Cauchi, T. Clarke, S. Enroth, K. Fischer, J. Hällfors, [...]& P. Elliott, KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference, Proc. Natl. Acad. Sci. U.S.A. 2016; 113 (50) 14372-14377.