HNF4α is a Crucial Modulator of the Cholesterol-Dependent Regulation of NPC1L1

Iwayanagi, Yuki; Takada, Tappei; Suzuki, Hiroshi

doi:10.1007/s11095-007-9496-9

Cited by 52 publications

(47 citation statements)

References 28 publications

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“…Regarding the regulatory mechanism of NPC1L1 expression, we demonstrated that, in addition to SREBP2, several transcriptional factors such as hepatocyte nuclear factor 4α (HNF4α/NR2A1), peroxisome proliferator-activated receptor α (PPARα/NR1C1), and PPARγ coactivator 1α (PGC1α) positively regulate the mRNA expression of NPC1L1. 15,49) Taken together with facts that both HNF4α and PPARα are involved in the pathogenesis of diabetes [50][51][52] and that intestinal expression of PGC1α is increased under diabetic conditions, 53) our findings indicate that these transcriptional factors may play important roles in the regulation of NPC1L1 expression under diabetic conditions and at least partly account for clinical associations between progressions of T2DM and other cholesterol-related diseases such as dyslipidemia and NAFLD/ NASH. 54,55) …”

Section: Npc1l1 and T2dmsupporting

confidence: 56%

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Associations between Lifestyle-Related Diseases and Transporters Involved in Intestinal Absorption and Biliary Excretion of Cholesterol

Yamanashi

Takada

Suzuki

2018

Biological & Pharmaceutical Bulletin

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Westernization of dietary habits leads to an increase in lipid intake and is thought to be responsible for an increase in patients with dyslipidemia. It is a well-known fact that the impaired cholesterol homeostasis is closely related to the development of various lifestyle-related diseases such as fatty liver, diabetes, and gallstone as well as dyslipidemia leading to atherosclerosis and cardiovascular diseases such as heart attack and stroke. Therefore, appropriate management of cholesterol levels in the body is considered important in prevention and treatments of these lifestyle-related diseases and in addition, molecular mechanisms controlling plasma (and/or hepatic) cholesterol levels have been intensively studied. Due to its hydrophobicity, cholesterol was long believed to pass through cell membranes by passive diffusion. However, recent studies have identified a number of plasma membrane transporters that are responsible for the cellular uptake or efflux of cholesterol and involved in developments of lifestyle-related diseases. In this review, we focus on Niemann-Pick C1 Like 1 (NPC1L1) and a heterodimer of ATP-binding cassette transporter G5 and G8 (ABCG5/G8), both of which are responsible for intestinal cholesterol absorption and biliary cholesterol secretion, and discuss the relationship between these cholesterol transporters and lifestyle-related diseases. In addition, we also discuss the related uncertainties that need to be explored in future studies.

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Section: Npc1l1 and T2dmsupporting

confidence: 56%

“…14,15) Since SREBP2 is activated when intracellular cholesterol level is decreased, NPC1L1 expression increases in response to cholesterol deficiency via the SREBP2-mediated transcription. In addition to the expression level, cellular localization of NPC1L1 protein is also regulated by cholesterol.…”

Section: Npc1l1 and Dyslipidemiamentioning

confidence: 99%

Associations between Lifestyle-Related Diseases and Transporters Involved in Intestinal Absorption and Biliary Excretion of Cholesterol

Yamanashi

Takada

Suzuki

2018

Biological & Pharmaceutical Bulletin

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“…It is, however, important to note that the contribution of other pathways beside DNA methylation in dictating the differential expression of intestinal NPC1L1 is also possible. For example, various transcription factors such as SREBP2 and HNF1␣ are known to modulate NPC1L1 expression (7,8). These and other transcription factors may play a role in its distribution along the duodenal-colonic axis.…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, NPC1L1 expression has been shown to be modulated at the transcriptional level. For example, SREBP2 and HNF4␣ transcription factors have been shown to stimulate NPC1L1 promoter activity and increase its mRNA expression (7,8). Because the expression of these transcription factors is not intestinal segment-specific (9, 10), their effects on gene transcription may not explain the region-specific expression of intestinal NPC1L1 mRNA.…”

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confidence: 99%

Epigenetic Modulation of Intestinal Cholesterol Transporter Niemann-Pick C1-like 1 (NPC1L1) Gene Expression by DNA Methylation

Malhotra

Soni

Kumar

et al. 2014

Journal of Biological Chemistry

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Background: Cholesterol transporter NPC1L1 is expressed in small intestine but not in colon. Results: DNA in the mouse NPC1L1 gene is hypermethylated in colon as compared with small intestine. DNA methylation decreases the promoter activity of NPC1L1. Conclusion: DNA hypermethylation may be responsible for silencing NPC1L1 expression in the colon. Significance: Altering DNA methylation may represent a novel mechanism to modulate NPC1L1 expression and cholesterol absorption.

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“…NPC1L1 の転写調節に関しては， sterol responsive element binding protein 2（SREBP2) 13,14) 及び hepatocyte nuclear factor 4a（HNF4a) 14 …”

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Transporter-mediated Regulation of Pharmacokinetics of Lifestyle-related Substances

Takada

2013

YAKUGAKU ZASSHI

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Recent studies revealed the importance of transporters in the behaviors of small molecules in the body. In mammals, the presence of a lot of transporters has been suggested, such as ATP-binding cassette (ABC) transporters and solute ligand carrier (SLC) transporters, some of which are clariˆed to be causative genes for various kinds of genetic disorders. In addition, a lot of transporters are known to mediate cellular import or export of drugs, to contribute to the pharmacokinetics of substrate drugs and to be involved in the interindividual diŠerences of drug responses. In this review, I introduce our recent work on the transporter-mediated regulation of pharmacokinetics of lifestyle-related substances, such as cholesterol and urate.

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HNF4α is a Crucial Modulator of the Cholesterol-Dependent Regulation of NPC1L1

Abstract: It is concluded that HNF4alpha plays a crucial role in the expression and regulation of human NPC1L1 gene.

Cited by 52 publications

References 28 publications

Associations between Lifestyle-Related Diseases and Transporters Involved in Intestinal Absorption and Biliary Excretion of Cholesterol

Associations between Lifestyle-Related Diseases and Transporters Involved in Intestinal Absorption and Biliary Excretion of Cholesterol

Epigenetic Modulation of Intestinal Cholesterol Transporter Niemann-Pick C1-like 1 (NPC1L1) Gene Expression by DNA Methylation

Transporter-mediated Regulation of Pharmacokinetics of Lifestyle-related Substances

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