What is Familial Hypercholesterolemia?
 

Familial Hypercholesterolemia (FH) is the most common autosomal dominant genetic disorder, primarily caused by pathogenic variants in genes such as LDLR, APOB, PCSK9, or LDLRAP1. Its main manifestation is a significant elevation in low-density lipoprotein cholesterol (LDL-C) levels, which, if left untreated, leads to atherosclerotic cardiovascular disease.

FH is classified into heterozygous (HeFH) and homozygous (HoFH) forms. The prevalence of HeFH is approximately 1 in 500, while HoFH is a rare disease with a prevalence typically ranging from 1/160,000 to 1/300,000.
 

Cholesterol Metabolism
 

To understand FH, it is essential to grasp the normal process of cholesterol metabolism. Human cholesterol originates from two primary sources: dietary cholesterol intake and endogenous cholesterol synthesis, with the liver contributing the vast majority of the body's cholesterol.
 

Cholesterol metabolism is essentially a dynamic equilibrium involving bidirectional flux between the liver and peripheral tissues. In peripheral tissues, excess cholesterol is transferred to High-Density Lipoprotein (HDL), forming mature HDL. Subsequently, the liver selectively uptakes HDL or Low-Density Lipoprotein (LDL) from the bloodstream via specific receptors (e.g., LDLR). Concurrently, the liver packages its own synthesized cholesterol into Very Low-Density Lipoproteins (VLDL) for release into the blood, where it is utilized by peripheral tissues. This HDL-mediated reverse cholesterol transport mechanism, combined with hepatic LDL clearance, maintains systemic cholesterol homeostasis.

 

Image source: Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease
 

Pathogenesis
 

The pathogenesis of FH is predominantly driven by specific gene mutations. Variants in the LDLRgene are the most common cause (accounting for 80–85% of FH cases), followed by APOB(5–10%), PCSK9(2%), and LDLRAP1(<1%). Notably, homozygous LDLRAP1variants typically lead to a different condition—Autosomal Recessive Hypercholesterolemia (ARH).

 

Image source: Genetic and molecular architecture of familial hypercholesterolemia
 

LDLR Mutation:​ The core principle of FH caused by LDLRgene mutations is loss of receptor function, leading to impaired hepatic clearance of LDL. Under normal circumstances, LDLR on hepatocyte surfaces is responsible for internalizing LDL from the blood for degradation, thereby maintaining lipid homeostasis. Once a mutation occurs (e.g., deletion, nonsense, or splice-site mutation), the synthesis, trafficking, binding, or recycling of the receptor protein is hindered. Consequently, LDL cannot be properly taken up and accumulates massively in the bloodstream, triggering persistent hypercholesterolemia and atherosclerosis.
 

APOB Mutation:​ APOBgene mutations result in insufficient binding to LDLR. Typically, LDL-C levels induced by pathogenic APOBvariants are lower than those caused by LDLRpathogenic variants.
 

PCSK9 Mutation:​ PCSK9mutations are categorized into Loss-of-Function (LOF) and Gain-of-Function (GOF) types. LOF variants produce poorly active proteins, whereas GOF variants yield more active proteins. GOF variants are associated with elevated LDL-C levels because they enhance the affinity for LDLR both extracellularly and accelerate LDLR degradation intracellularly. This leads to reduced LDLR expression on the cell membrane and subsequent plasma LDL accumulation.
 

LDLRAP1 Mutation:​ Mutations in LDLRAP1represent a key defect in the LDL receptor (LDLR) cycling process, causing Autosomal Recessive Hypercholesterolemia. These mutations impair the internalization of the LDLR-LDL complex.
Dysfunctional LDLRAP1 fails to properly form clathrin-coated endosomes, inhibiting the uptake of Low-Density Lipoprotein (LDL) and thereby increasing plasma LDL-C accumulation.
 

Image source: Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease
 

Atherosclerosis
 

Based on the aforementioned mechanisms, FH patients suffer from persistently elevated blood LDL-C levels due to defects in LDLRand other functions. Excess cholesterol becomes a core driver of atherosclerosis. These lipids traverse the vascular endothelium, become trapped within the arterial wall, and undergo oxidative modification, triggering a chronic inflammatory response. Driven by inflammatory signals, monocytes are recruited to the sub-endothelial space, differentiate into macrophages, and massively phagocytose oxidized lipids, transforming into foam cells. The aggregation of numerous foam cells constitutes the lipid core of atherosclerotic plaques, while vascular smooth muscle cells migrate and secrete collagen to form a fibrous cap covering the plaque.
 

As the disease progresses, persistent inflammation within the plaque leads to expansion of the lipid core and thinning of the fibrous cap, decreasing stability. Unstable plaques may rupture, exposing pro-coagulant materials that trigger platelet aggregation and thrombus formation, ultimately resulting in atherothrombosis.
 

 

Image source: Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease
 

Common Mouse Models
 

LDLR⁻/⁻ Mice:​ Knockout of the LDLRgene, modeling severely impaired hepatic clearance of LDL-C and significant elevation of plasma cholesterol. These mice often require a high-fat diet to accelerate atherosclerosis plaque formation and are widely used to explore FH pathogenesis.
 

APOE⁻/⁻ Mice:​ Knockout of the APOEgene, modeling lipoprotein metabolism disorders. They are primarily used to study the inflammatory immune mechanisms of atherosclerosis and the fundamental pathways of lipid metabolism.
 

PCSK9 Humanized Mice:​ Full-length replacement of the mouse Pcsk9gene with the human PCSK9gene sequence, ensuring specific expression of human PCSK9 in mice. Suitable for cholesterol metabolism research and the development of PCSK9-targeted gene therapies.
 

Supporting Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation rely heavily on animal model support. MingCeler Biotech, leveraging its self-developed TurboMice™ technology, has developed multiple rare disease mouse models. TurboMice™ technology overcomes the technical challenges of long mouse model generation cycles and low success rates for complex models, enabling editing at almost any target gene locus. Complete homozygous gene-edited mouse models can be prepared directly from embryonic stem cells in as little as two months.
 

MingCeler Biotech​ can customize various FH mouse models according to client needs, such as LDLR⁻/⁻ mice, APOE⁻/⁻ mice, and PCSK9 humanized mice. Notably, PCSK9 humanized mice can be supplied in batches in as little as two months.
Inquiries are welcome.
 

References:
 

1.Benito-Vicente A, Uribe KB, Jebari S, Galicia-Garcia U, Ostolaza H, Martin C. Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease. Int J Mol Sci. 2018 Nov 1;19(11):3426. doi: 10.3390/ijms19113426. PMID: 30388787; PMCID: PMC6275065.

2.Abifadel M, Boileau C. Genetic and molecular architecture of familial hypercholesterolemia. J Intern Med. 2023 Feb;293(2):144-165. doi: 10.1111/joim.13577. Epub 2022 Oct 17. PMID: 36196022; PMCID: PMC10092380.

3.Suryawanshi YN, Warbhe RA. Familial Hypercholesterolemia: A Literature Review of the Pathophysiology and Current and Novel Treatments. Cureus. 2023 Nov 20;15(11):e49121. doi: 10.7759/cureus.49121. PMID: 38125244; PMCID: PMC10732334.