Control of ACAT2 liver expression by HNF1

Pramfalk, Camilla; Davis, Matthew; Eriksson, Mats; Rudel, Lawrence L.; Parini, Paolo

doi:10.1194/jlr.m400450-jlr200

Cited by 30 publications

(37 citation statements)

References 29 publications

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“…HuH7 cells were cultured as described ( 20 ). Caco2 cells were grown in DMEM supplemented with 20% FBS, 100 U/ml penicillin, and 100 µg/ml streptomycin; the media were replaced every second day.…”

Section: Journal Of Lipid Research Volume 55 2014mentioning

confidence: 99%

TG-interacting factor 1 acts as a transcriptional repressor of sterol O-acyltransferase 2

Pramfalk

Melhuish

Wotton

et al. 2014

Journal of Lipid Research

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Section: Journal Of Lipid Research Volume 55 2014mentioning

confidence: 99%

TG-interacting factor 1 acts as a transcriptional repressor of sterol O-acyltransferase 2

Pramfalk

Melhuish

Wotton

et al. 2014

Journal of Lipid Research

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“…HNF4 ␣ is an upstream regulator of HNF1 ␣ , and both contain binding sites for each other in their promoter region ( 26,29 ), suggesting a reciprocal regulation. HNF1 ␣ was recently shown to be an important regulator of ACAT2 ( 19 ), which is another important gene involved in cholesterol homeostasis. By coimmunoprecipitation of nuclear extracts from human liver with an antibody raised against HNF1 ␣ and detection by Western blot with an HNF4 ␣ antibody, we were able to show that a protein-protein interaction between HNF4 ␣ and HNF1 ␣ occurs in human liver ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

“…HuH7 and HEK293 cells were cultured as described ( 19 ). For all cell experiments, HuH7 or HEK293 cells were plated out on 6-well tissue culture plates so that they reached ‫ف‬ 70% confl uence after 24 h (i.e., ‫ف‬ 700,000 cells/well).…”

mentioning

confidence: 99%

“…The chromatin immunoprecipitation (ChIP) assays were performed using ‫ف‬ 200 mg liver from a healthy donor as described ( 19 ). Specifi c antibodies for HNF1 ␣ (sc-6547×; Santa Cruz Biotechnology), SREBP2 (sc-8151×; Santa Cruz Biotechnology), and an IgG antibody (sc-2027; Santa Cruz Biotechnology), as a (baseline) control, were used (4 µg).…”

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confidence: 99%

“…For all cell experiments, HuH7 or HEK293 cells were plated out on 6-well tissue culture plates so that they reached ‫ف‬ 70% confl uence after 24 h (i.e., ‫ف‬ 700,000 cells/well). The human NPC1L1 promoter ( Ϫ 1570 to +137) was screened using the transcription factor TESS database ( www.cbil.upenn.edu at University of Pennsylvania, Philadelphia, PA) to search for putative HNF1 binding sites, and specifi c point mutations were generated as described (primer sequences are available upon request) ( 19 ).…”

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HNF1α and SREBP2 are important regulators of NPC1L1 in human liver

Pramfalk

Jiang

Cai

et al. 2010

Journal of Lipid Research

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This article is available online at http://www.jlr.org target of the cholesterol-lowering drug ezetimibe ( 1, 2 ). Mice defi cient in NPC1L1 have ‫ف‬ 70% reduction in cholesterol absorption ( 1 ) and resistance to diet-induced hypercholesterolemia ( 3 ). NPC1L1 is widely expressed in many human tissues, with the highest expression in small intestine and in the liver ( 3, 4 ). In mice and rats, npc1l1 is predominantly expressed in the small intestine, whereas all others tissues showed expression levels <10% of the intestinal expression ( 1, 5 ). The exact function of NPC1L1 in the human liver is currently unknown. It was recently reported that NPC1L1 facilitates the uptake of free cholesterol from the culture medium in human ( 6 ) and rat ( 7 ) hepatoma cells. Previous reports also showed that NPC1L1 localizes to the canalicular membrane in hepatocytes ( 6,8 ). Transgenic mice overexpressing human NPC1L1 in the liver had dramatically decreased biliary cholesterol concentration, which was returned to normal with ezetimibe treatment ( 8 ). This suggests that hepatic NPC1L1 could be another target of ezetimibe in humans.Several genes involved in cholesterol synthesis and uptake are regulated by sterol regulatory element binding protein 2 (SREBP2). Activation of SREBP2 is dependent on the cholesterol status of the cell ( 9 ). When cellular cholesterol levels are low, SREBP2 is proteolytically cleaved to release the N-terminal portion to generate the mature form that can enter the nucleus and bind to sterol regulatory elements (SREs) or E-boxes in the promoter of various genes and affect gene expression ( 9, 10 ).Hepatic nuclear factors (HNFs) 1 and 4 are expressed in various organs, including the liver, intestine, and panAbstract Niemann-Pick C1-like 1 (NPC1L1), a key regulator of intestinal cholesterol absorption, is highly expressed in human liver. Here, we aimed to gain more insight into mechanisms participating in its hepatic regulation in humans. Correlation analysis in livers from Chinese patients with and without gallstone disease revealed strong positive correlations between NPC1L1 and sterol regulatory element binding protein 2 (SREBP2) ( r = 0.74, P < 0.05) and between NPC1L1 and hepatic nuclear factor ␣ (HNF4 ␣ ) ( r = 0.53, P < 0.05) mRNA expression. HNF4 ␣ is an upstream regulator of HNF1 ␣ ; thus, we also tested whether HNF1 ␣ participates in the regulation of NPC1L1. We showed a dose-dependent regulation by SREBP2 on the NPC1L1 promoter activity and mRNA expression in HuH7 cells. Chromatin immunoprecipitation assay confi rmed the binding of SREBP2 to the promoter in vivo. Surprisingly, HNF4 ␣ slightly decreased the NPC1L1 promoter activity but had no effect on its gene expression. By contrast, HNF1 ␣ increased the promoter activity and the gene expression, and an important HNF1 binding site was identifi ed within the human NPC1L1 promoter. ChIP assays confi rmed that HNF1 ␣ can bind to the NPC1L1 promoter in vivo. Niemann-Pick C1-like 1 (NPC1L1) is a key regulator of intestinal cholesterol absorption a...

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Cholesteryl esters and ACAT

Pramfalk

Eriksson

Parini

2012

Euro J Lipid Sci & Tech

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Acyl-coenzyme A:cholesterol acyltransferase (ACAT) 1 and 2 are both involved in intracellular cholesterol esterification. The expression of acyl-coenzyme A:cholesterol acyltransferase 1; (ACAT1) is ubiquitous, whereas, enterocytes and hepatocytes exclusively express acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2). Studies in mice lacking ACAT1 showed extensive deposition of unesterified cholesterol in skin and brain, and larger atherosclerotic lesions compared to controls. ACAT2 deficiency in mice protected against atherosclerosis, diet-induced hypercholesterolemia and cholesterol gallstone disease, and reduced hepatic lipid accumulation and decreased serum cholesterol levels. Two unspecific ACAT inhibitors have been tested in humans. In the face of the results in ACAT1 deficient mice, strongly arguing against an ACAT1 inhibition, it was not surprising that none of these inhibitors showed beneficial effects on the predefined primary endpoints of the studies. However, and still to be proven, ACAT2 inhibition might be a therapeutic option for the treatment and prevention of cardiovascular disease. In this review, we aim to outline some important aspects on the role of ACAT in cholesterol esterification and to reappraise ACAT2 as therapeutic target.

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Control of ACAT2 liver expression by HNF1

Cited by 30 publications

References 29 publications

TG-interacting factor 1 acts as a transcriptional repressor of sterol O-acyltransferase 2

TG-interacting factor 1 acts as a transcriptional repressor of sterol O-acyltransferase 2

HNF1α and SREBP2 are important regulators of NPC1L1 in human liver

Cholesteryl esters and ACAT

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