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Published on: November 17, 2018
Hepatocyte nuclear factor-4α, a multifunctional nuclear receptor associated with cardiovascular disease and
Olga Lidia Tavares-Sanchez1, Carmen Rodriguez, Pablo Gortares-Moroyoqui
1a Departamento de Biotecnología y Ciencias Alimentarias , Instituto Tecnológico de Sonora , Ciudad Obregón , Mexico.
Insights
Hepatocyte nuclear factor-4α (HNF-4α) plays a key role in converting cholesterol to bile acids, a major cholesterol elimination pathway. Understanding HNF-4α may offer new ways to manage cholesterol levels and reduce cardiovascular disease (CVD) risk.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiovascular Science
Background:
- Cardiovascular diseases (CVDs) are a leading global cause of death, often linked to high plasma cholesterol.
- Bile acid (BA) synthesis in the liver accounts for approximately 50% of cholesterol elimination.
- Hepatocyte nuclear factor-4α (HNF-4α) is a critical regulator of BA synthesis.
Purpose of the Study:
- To highlight the properties and multifunctional role of HNF-4α.
- To emphasize HNF-4α's role in cholesterol to BA conversion.
- To explore HNF-4α as a potential target for cholesterol management.
Main Methods:
- Focus on the regulatory functions of HNF-4α.
- Investigate HNF-4α's transactivation of genes involved in BA biosynthesis, such as CYP7A1.
- Examine the modulatory effects of phosphorylation on HNF-4α activity.
Main Results:
- HNF-4α is a conserved transcription factor with broad gene transactivation capacity.
- HNF-4α directly influences CYP7A1, the rate-limiting enzyme in BA biosynthesis.
- Phosphorylation is identified as a key mechanism for modulating HNF-4α's transactivation potential.
Conclusions:
- HNF-4α is central to cholesterol metabolism via bile acid synthesis.
- Further research into HNF-4α's structural and functional characteristics can lead to novel cholesterol-lowering strategies.
- Targeting HNF-4α may offer a therapeutic avenue for reducing CVD risk.
Abstract:
Cardiovascular diseases (CVDs), the leading cause of death worldwide, are associated with high plasma cholesterol levels. The conversion of cholesterol to bile acids (BAs) accounts for about 50% of total cholesterol elimination from the body. This phenomenon occurs in the liver and is regulated by nuclear receptors such as hepatocyte nuclear factor-4α (HNF-4α). Therefore, special emphasis is given to HNF-4α properties and its multifunctional role, particularly in the conversion of cholesterol to BAs. HNF-4α is a highly conserved transcription factor that has the potential capacity to transactivate a vast number of genes, including CYP7 which codes for cholesterol 7α-hydroxylase (CYP7A1; EC 1.14.13.17), the rate-limiting enzyme of BA biosynthesis. The fact that HNF-4α transactivation potential can be modulated via phosporylation is of particular interest. Additional findings on structural and functional characteristics of HNF-4α may eventually present alternatives to control the levels of cholesterol in the body and consequently reduce the risk of CVDs.
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