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Updated: Jun 22, 2026
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Cell Type-specific Gene Expression Profiling in the Mouse Liver
Published on: September 17, 2019
Control of ACAT2 liver expression by HNF4{alpha}: lesson from MODY1 patients
C Pramfalk1, E Karlsson, L Groop
1Division of Clinical Chemistry, Department of Laboratory Medicine, C1-74, Karolinska Institutet at Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden.
Arteriosclerosis, Thrombosis, and Vascular Biology
|May 30, 2009
Summary
Hepatocyte nuclear factor 4-alpha (HNF4alpha) regulates ACAT2, impacting VLDL and LDL cholesterol. MODY1 patients with HNF4alpha mutations show reduced esterified cholesterol in these lipoproteins, suggesting lower ACAT2 activity.
Area of Science:
- Molecular biology
- Lipid metabolism
- Genetics
Background:
- Acyl-CoA:cholesterol acyltransferase 2 (ACAT2) is crucial for cholesteryl ester production in VLDL and chylomicron assembly.
- Hepatocyte nuclear factor 1-alpha (HNF1alpha) has been identified as a key regulator of the human ACAT2 promoter.
- Hepatocyte nuclear factor 4-alpha (HNF4alpha) is an upstream regulator of HNF1alpha.
Purpose of the Study:
- To investigate the role of HNF4alpha and HNF1alpha in regulating ACAT2 expression.
- To determine if mutations in HNF1alpha (MODY3) or HNF4alpha (MODY1) affect VLDL esterified cholesterol levels.
Main Methods:
- Serum analysis and lipoprotein separation via size-exclusion chromatography in controls, MODY1, and MODY3 subjects.
- In vitro studies including mutagenesis and cotransfections in HuH7 cells.
- In vivo validation using ChIP assays in human liver and protein-to-protein interaction studies.
Main Results:
- MODY3 patients exhibited normal lipoprotein composition.
- MODY1 patients displayed reduced levels of VLDL and LDL esterified cholesterol, and VLDL triglyceride.
- HNF4alpha was identified as a direct or indirect regulator of the ACAT2 promoter, binding to a specific site.
Conclusions:
- HNF4alpha is a significant regulator of hepatocyte-specific ACAT2 gene expression.
- Reduced ACAT2 activity in MODY1 patients likely contributes to lower esterified cholesterol levels in VLDL and LDL particles.
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