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Updated: May 3, 2026
A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
Published on: September 15, 2018
Subjects with familial hypercholesterolemia are characterized by an inflammatory phenotype despite long-term
Kirsten B Holven1, Ingunn Narverud2, Henriette W Lindvig3
1Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway.
Insights
Long-term statin treatment did not normalize inflammatory responses in Familial Hypercholesterolemia (FH) patients. Gene expression of tumor necrosis factor (TNF) related molecules and TNFα release remained elevated in FH patients, suggesting a role for inflammation beyond lipid levels.
Area of Science:
- Cardiovascular Medicine
- Immunology
- Genetics
Background:
- Familial Hypercholesterolemia (FH) is characterized by elevated Low-density lipoprotein (LDL)-cholesterol and increased inflammatory responses, contributing to premature atherosclerosis.
- While statins effectively lower LDL-cholesterol, their impact on inflammatory pathways in FH patients is not fully understood.
Purpose of the Study:
- To investigate whether long-term statin therapy normalizes inflammatory responses in FH patients.
- To analyze the expression of tumor necrosis factor (receptor) superfamily genes and TNFα release in peripheral blood mononuclear cells (PBMC) of statin-treated FH patients.
Main Methods:
- Real-time quantitative RT-PCR was used to analyze gene expression of TNF superfamily members in PBMC from 33 long-term statin-treated FH subjects and 10 healthy controls.
- Tumor necrosis factor alpha (TNFα) release was quantified using immunoassay in PBMC from both groups.
Main Results:
- FH patients on statins showed increased gene expression of CD137, LIGHT, HVEM, TNFR1, TNFR2, TRAIL, and CD40 in PBMC compared to controls.
- PBMC from FH patients exhibited elevated TNFα release in response to lipopolysaccharide (LPS) and enhanced spontaneous TNFα release, particularly with FH serum.
- These inflammatory markers were elevated despite normalized LDL-cholesterol levels after a median of 17 years of statin treatment.
Conclusions:
- Long-term statin therapy does not normalize the expression of several TNF-related genes or TNFα release in FH patients.
- These findings suggest a significant pathogenic role for inflammation and TNF-related molecules in FH, independent of LDL-cholesterol levels.
- Novel therapeutic strategies targeting inflammation beyond lipid-lowering may be beneficial for FH patients.
Objective:
The atherosclerotic process is driven by elevated Low-density lipoprotein (LDL)-cholesterol in combination with enhanced inflammatory responses. Several mediators participate in this complex inflammatory network including members of the tumour necrosis factor (receptor) superfamily. Familial hypercholesterolemia (FH) is associated with increased risk of developing premature atherosclerosis. Statin treatment may normalize LDL-cholesterol levels, but it is not known if the inflammatory responses are normalized in statin-treated FH patients.
Methods:
In long-term statin-treated FH subjects (n=33) and healthy controls (n=10) the expression of tumour necrosis factor (receptor) superfamily related genes in peripheral blood mononuclear cells (PBMC) were analyzed by real-time quantitative RT-PCR. TNFα release was measured in PBMC from patients and controls by immunoassay.
Results:
In FH patients with normal LDL-cholesterol, after a median of 17 years of statin treatment, our major findings were: (i) Gene expression of CD137, LIGHT (lymphotoxins inducible expression, competes with HSV glycoprotein D for HVEM, a receptor expressed on T-lymphocytes), HVEM (Herpesvirus entry mediator), the two TNFα Receptors (TNFR1 and TNFR2), TNF related apoptosis inducing ligand (TRAIL) and CD40 were increased in PBMC from FH patients compared to controls. (ii) The release of TNFα in PBMC from FH patients, in response to LPS was increased compared to controls. (iii) PBMC from FH patients had enhanced spontaneous release of TNFα when incubated in the presence of control serum and in particular in the presence of FH serum.
Conclusion:
Despite long-term statin therapy, an increased expression of several TNF related genes in PBMC isolated from FH patients was observed. Our findings may implicate a pathogenic role for inflammation and TNF related molecules in FH, and these findings suggest the possibility that novel treatment modalities beyond that of statins and lipid lowering drugs may be useful in FH subjects.
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