Hepatocyte nuclear factor-4α, a multifunctional nuclear receptor associated with cardiovascular disease and cholesterol catabolism

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.

Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability

“…HNF1A mutations cause maturity-onset diabetes of the young (MODY) type 3 (MODY3, OMIM #600496). The hepatocyte nuclear factor 4-alpha (HNF4A, Chr 20) is a regulator of CYP7A1 gene transcription among other genes [ 106 ]. HNF4A mutations cause MODY type 1 (MODY1, OMIM #125850).…”

Controversial roles of hepatocyte nuclear receptor 4 α on tumorigenesis (Review)

“…HNF4α is a highly conserved member of the nuclear receptor superfamily of ligand-dependent transcription factors, acts as a homodimer and plays a critical role in early liver morphogenesis, fatal liver development, liver differentiation and metabolism by regulating the transcription of genes involved in each of these biological processes (5,(16)(17)(18). Numerous studies have also reported the central role of HNF4α in regulating a number of genes, such as cytochrome P450 genes (CYP2C8, CYP2C9, CYP2C19, CYP7A1, CYP3A4 and CYP8B1) that essential for the xenobiotic and drug metabolism, to protect individuals from toxic effects and provide key building blocks and nutrients to promote the growth or maintain the survival of the organism (5,(19)(20)(21). Due to its multiple functions, HNF4α is described as a master regulator in multiple signal channels.…”

Metabolism and Toxicity of Emodin: Genome-Wide Association Studies Reveal Hepatocyte Nuclear Factor 4α Regulates UGT2B7 and Emodin Glucuronidation

“…9−12 HNF4A, known as an highly conserved transcription factor, highly regulates the conversion of cholesterol to bile acids and is therefore associated with cholesterol catabolism and cardiovascular disease. 13 HNF4A variants were identified to be susceptible to type 2 diabetes mellitus. 14,15 It was reported that HNF4A plays a key role in the regulation of drug metabolizing enzymes, such as UDP glucuronosyltransferase Family 1 Member A8, A9, and A10 (UGT1A8, -1A9, and -1A10).…”

“…The gene expression of UGTs can be controlled by nuclear receptors (NRs), such as hepatocyte nuclear factor 4α (HNF4A). HNF4A is a member of nuclear receptor superfamily and is highly expressed in liver and kidneys. − HNF4A, known as an highly conserved transcription factor, highly regulates the conversion of cholesterol to bile acids and is therefore associated with cholesterol catabolism and cardiovascular disease . HNF4A variants were identified to be susceptible to type 2 diabetes mellitus. , It was reported that HNF4A plays a key role in the regulation of drug metabolizing enzymes, such as UDP glucuronosyltransferase Family 1 Member A8, A9, and A10 (UGT1A8, -1A9, and -1A10). , The specific disruption of HNF4A gene in mouse liver can obviously reduce liver UGT1A9 gene expression, and HNF4A was demonstrated to activate the UGT1A9 promoter …”