Alb-hLPA/B6-TG(APOB) Mice

Catalog Number: C001591

Strain Name: C57BL/6N;C57BL/6JCya-Igs2em1(Alb-hLPA)Tg(hAPOB)/Cya

Genetic Background: C57BL/6N;C57BL/6JCya

Reproduction: Homozygous H11-Alb-hLPA x Alb-hLPA/B6-TG(APOB)

 

Strain Description

Lipoprotein(a) (Lp(a)) is a lipoprotein particle consisting of apolipoprotein(a) (Apo(a)) bound to low-density lipoprotein (LDL) containing apolipoprotein B (ApoB), where the LPA gene encoding for Apo(a) is only found in the genomes of humans and some non-human primates. LP(a) is similar in size and lipid content to low-density lipoprotein (LDL) and is considered a new risk factor for several cardiovascular diseases (CVD), including atherosclerosis, coronary heart disease, and stroke [1]. Lp(a) differs from LDL in that it contains an additional variable-length Apo(a), which covalently binds to ApoB-100 via a single disulfide bond. Lp(a) plays a crucial role in systemic lipid transport, guiding inflammatory cells into blood vessel walls and promoting smooth muscle cell proliferation. Additionally, it participates in wound healing and tissue repair, interacting with components of the blood vessel wall and extracellular matrix [2]. However, Lp(a) can also cause arterial narrowing by adhering to the arterial wall, accelerating blood clot formation, and triggering pathological changes related to coronary heart disease, atherosclerosis, thrombosis, and stroke [3]. The plasma concentration of Lp(a) is closely related to genetic factors, primarily regulated by the LPA gene. Consequently, the LPA gene represents an important potential target for cardiovascular disease treatment. Currently, several novel therapies aimed at modulating LPA gene transcription rates are under development, including small interfering RNA (siRNA) and antisense oligonucleotide (ASO) drugs [4]. Since the LPA gene is expressed only in humans and some non-human primates but not in mice, constructing a mouse model expressing the human LPA gene is crucial for the preclinical evaluation of lipid-lowering drugs.

Apolipoprotein B (APOB) is a key protein in lipid metabolism and cardiovascular disease (CVD). It is the primary apolipoprotein of low-density lipoprotein (LDL), lipoprotein (a) (Lp(a)), very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and chylomicrons (CM), responsible for transporting fat molecules, including cholesterol, throughout the body [5]. Cholesterol and other lipids can accumulate in arteries, promoting plaque formation, reducing blood flow, and increasing the risk of myocardial infarction, stroke, and other cardiovascular events. High levels of ApoB are a major contributor to plaque formation in vascular diseases such as atherosclerosis [6]. There are two main subtypes of ApoB protein in plasma: ApoB48 and ApoB100. ApoB48 is synthesized only in the small intestine and is the primary apolipoprotein of intestinal chylomicrons. ApoB100 is synthesized by the liver, composed of 4563 amino acids, and is the largest and most abundant subtype of ApoB protein. ApoB48 is produced by tissue-specific RNA editing and comprises 48% of the ApoB100 sequence. It has the same N-terminal sequence as ApoB100 but lacks the C-terminal LDL receptor-binding region. In CVD, ApoB100 is the main driver. The number of ApoB100 particles in the blood reflects the total number of atherosclerotic particles, while traditional cholesterol tests only measure the amount of cholesterol carried by these particles. Therefore, ApoB100 levels are a strong predictor of atherosclerotic cardiovascular disease risk [7].

The Alb-hLPA/B6-TG(APOB) mouse is a dual humanized model obtained by crossing H11-Alb-hLPA mice (Catalog No.: C001542) with B6-Tg (APOB) mice (Catalog No.: C001435). This model includes two cardiovascular disease risk factors, LP(a) and ApoB, and is suitable for the study of hyperlipidemia, stroke, coronary heart disease, familial hypercholesterolemia (FH), and other atherosclerotic cardiovascular diseases (ASCVD).

Strain strategy

Obtained by crossing H11-Alb-hLPA mice (Catalog No.: C001542) with B6-Tg (APOB) mice (Catalog No.: C001435).

 

Application

  • Development and evaluation of LP(a) and ApoB targeted drugs;
  • Research on familial hypercholesterolemia (FH);
  • Research on atherosclerotic cardiovascular disease (ASCVD);
  • Research on other cardiovascular diseases (CVD).

 

Validation Data

1. Levels of human Lipoprotein A (LP(a)) 


Figure 1. Detection of human lipoprotein A (LPA) levels in Alb-hLPA/B6-TG(APOB) mice (nELISA≥5, nBlood Biochemistry≥5). ELISA and blood biochemistry results indicate that male and female Alb-hLPA/B6-TG(APOB) mice successfully express human LPA protein, with males exhibiting higher LPA levels than females (Bars represent mean ± SD).

 

2. Levels of human Apolipoprotein B (ApoB)


Figure 2. Detection of human ApoB protein levels in Alb-hLPA/B6-TG(APOB) mice (nELISA≥5, nBlood Biochemistry≥5). ELISA and blood biochemistry results indicate that male and female Alb-hLPA/B6-TG(APOB) mice successfully express human ApoB protein (Bars represent mean ± SD).

 

3. Lipid Metabolism & Liver Function


Figure 3. Blood lipid parameters in Alb-hLPA/B6-TG(APOB) mice and wild-type (WT) mice (n=5). Blood biochemistry results indicate that T-CHO, TG, and LDL-C levels in Alb-hLPA/B6-TG(APOB) mice are significantly higher than in WT mice, while AST levels are significantly lower in Alb-hLPA/B6-TG(APOB) mice. No significant differences were observed for the other parameters (Bars represent mean ± SEM).

*T-CHO: Total cholesterol; TG: Triglycerides; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase.

 

References
[1]Kronenberg F. Lipoprotein(a). Handb Exp Pharmacol. 2022;270:201-232.
[2]Brown MS, Goldstein JL. Plasma lipoproteins: teaching old dogmas new tricks. Nature. 1987 Nov 12-18;330(6144):113-4.
[3]Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG. Lipoprotein(a) and risk of myocardial infarction--genetic epidemiologic evidence of causality. Scand J Clin Lab Invest. 2011 Apr;71(2):87-93.
[4]Alebna, P. L., & Mehta, A. (2023, September 19). An Update on Lipoprotein(a): The Latest on Testing, Treatment, and Guideline Recommendations. American College of Cardiology. https://www.acc.org/latest-in-cardiology/articles/2023/09/19/10/54/an-update-on-lipoprotein-a
[5]Glavinovic T, Thanassoulis G, de Graaf J, Couture P, Hegele RA, Sniderman AD. Physiological Bases for the Superiority of Apolipoprotein B Over Low-Density Lipoprotein Cholesterol and Non-High-Density Lipoprotein Cholesterol as a Marker of Cardiovascular Risk. J Am Heart Assoc. 2022 Oct 18;11(20):e025858.
[6]Sniderman AD, Thanassoulis G, Glavinovic T, Navar AM, Pencina M, Catapano A, Ference BA. Apolipoprotein B Particles and Cardiovascular Disease: A Narrative Review. JAMA Cardiol. 2019 Dec 1;4(12):1287-1295.
[7]Behbodikhah J, Ahmed S, Elyasi A, Kasselman LJ, De Leon J, Glass AD, Reiss AB. Apolipoprotein B and Cardiovascular Disease: Biomarker and Potential Therapeutic Target. Metabolites. 2021 Oct 8;11(10):690.