Hepatocyte ATF3 protects against atherosclerosis by regulating HDL and bile acid metabolism.
atherosclerosis
Activating transcription factor (ATF)3 is known to have an anti-inflammatory function, yet the role of hepatic ATF3 in lipoprotein metabolism or atherosclerosis remains unknown. Here we show that overexpression of human ATF3 in hepatocytes reduces the development of atherosclerosis in Western-diet-fed Ldlr(-/-) or Apoe(-/-) mice, whereas hepatocyte-specific ablation of Atf3 has the opposite effect. We further show that hepatic ATF3 expression is inhibited by hydrocortisone. Mechanistically, hepatocyte ATF3 enhances high-density lipoprotein (HDL) uptake, inhibits intestinal fat and cholesterol absorption and promotes macrophage reverse cholesterol transport by inducing scavenger receptor group B type 1 (SR-BI) and repressing cholesterol 12α-hydroxylase (CYP8B1) in the liver through its interaction with p53 and hepatocyte nuclear factor 4α, respectively. Our data demonstrate that hepatocyte ATF3 is a key regulator of HDL and bile acid metabolism and atherosclerosis.
Xu Y;Li Y;Jadhav K;Pan X;Zhu Y;Hu S;Chen S;Chen L;Tang Y;Wang HH;Yang L;Wang DQ;Yin L;Zhang Y
Nature Metabolism
2021
2021-01
journalArticle
<a href="http://doi.org/10.1038/s42255-020-00331-1" target="_blank" rel="noreferrer noopener">10.1038/s42255-020-00331-1</a>
Cross-talk Between Nmda And Gaba(a) Receptors In Cultured Neurons Of The Rat Inferior Colliculus
acid type A receptor; calcium influx; cross-talk; currents; dependent protein-kinase; dorsal-horn neurons; gamma-aminobutyric; gamma-aminobutyric-acid; glycine receptors; granule cells; inferior colliculus; intracellular ca2+; Life Sciences & Biomedicine - Other Topics; N-methyl-D-aspartate receptor; pyramidal cells; responses; whole-cell patch-clamp
Cong D N; Tang Z Q; Li L Z; Huang Y N; Wang J; Chen L
Science China-Life Sciences
2011
2011-06
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1007/s11427-011-4178-6" target="_blank" rel="noreferrer noopener">10.1007/s11427-011-4178-6</a>
THE HUMAN CYP4F2 GENE CDNA SEQUENCE AND CATALYTIC ACTIVITY OF BACULOVIRUS-INFECTED INSECT CELLS
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Chen L; Hardwick J P
Faseb Journal
1994
1994-04
Journal Article or Conference Abstract Publication
n/a
Proximal promoter structure and transcriptional regulation of the CYP4F2 human liver leukotriene B-4 omega-hydroxylase gene
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Zhang X; Chen L; Hardwick J P
Faseb Journal
1999
1999-04
Journal Article
n/a
PHYSICOCHEMICAL CHARACTERIZATION OF AQUEOUS LIPID PHASES OF RELEVANCE TO INTESTINAL FAT DIGESTION AND ABSORPTION - A H-2 NMR AND X-RAY-DIFFRACTION STUDY
Biophysics
Westerman P W; Chen L
Biophysical Journal
1993
1993-02
Journal Article
n/a
Something completely different?
Animals; Blotting; Brain/*enzymology; Cloning; Complementary; Cytochrome P-450 Enzyme System/*genetics/isolation & purification; DNA; Kidney/enzymology; Liver/enzymology; Molecular; Northern; Rats
Hardwick J P; Chen L
Human & experimental toxicology
1996
1996-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1177/096032719601500616" target="_blank" rel="noreferrer noopener">10.1177/096032719601500616</a>
Promoter activity and regulation of the CYP4F2 leukotriene B(4) omega-hydroxylase gene by peroxisomal proliferators and retinoic acid in HepG2 cells.
*Gene Expression Regulation; *Promoter Regions; Amino Acid Sequence; Base Sequence; Cell Line; Cloning; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme System/*genetics/metabolism; Cytochrome P450 Family 4; Cytoplasmic and Nuclear/metabolism; DNA; DNA Footprinting; Enzymologic; Exons; Genes; Genetic; Genetic/drug effects; Humans; Introns; Leukotriene B4/metabolism; Mixed Function Oxygenases/metabolism; Models; Molecular; Molecular Sequence Data; Peroxisome Proliferators/*metabolism; Receptors; Reporter; Retinoic Acid Receptor alpha; Retinoic Acid/metabolism; Sequence Analysis; Transcription; Transcription Factors/metabolism; Transfection; Tretinoin/*metabolism
The human liver CYP4F2 gene (Accession No. AF221943) encodes a leukotriene B(4) omega-hydroxylase that metabolizes leukotriene B(4) (LTB(4)) to a less potent proinflammatory eicosanoid, 20-OH-LTB(4). We sequenced a 6.7-kb genomic fragment of the human CYP4F2 gene that has the first five exons and 500 bp of the 5'-flanking region. The major transcription start site was found to be 49 bp upstream of the 3' end of exon 1 and the ATG translation initiation codon was located in exon 2. Besides the TATA box at -39 bp and basal transcription factor binding sites, the promoter region and 412-bp intron 1 have several putative binding sites for nuclear factors that may mediate the inflammatory response and lipid homeostasis. We found two DR1 elements in the 5' promoter, a DR2 element in intron 1, and RXR/RAR binding sites in both intron 1 and the 5' promoter. DNase I footprinting revealed three protected sequences, with the region containing two CAATT boxes at -71 and -111 bp important in CYP4F2 gene expression. Luciferase reporter assays showed that the 500-bp upstream sequence has strong promoter activity. Transient transfection experiments identified two sites in the 5' promoter and intron 1 that cooperate in gene transcription while exon 1 and a
Zhang X; Chen L; Hardwick J P
Archives of biochemistry and biophysics
2000
2000-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1006/abbi.2000.1836" target="_blank" rel="noreferrer noopener">10.1006/abbi.2000.1836</a>
Identification of a new P450 subfamily, CYP4F1, expressed in rat hepatic tumors.
2-Acetylaminofluorene; Aflatoxin B1; Amino Acid; Amino Acid Sequence; Animals; Antisense Elements (Genetics); Base Sequence; Blotting; Clofibrate; Cytochrome P-450 Enzyme System/analysis/*genetics; Humans; Liver Neoplasms/chemically induced/*enzymology/genetics; Male; Microsomes/enzymology; Molecular Sequence Data; Multigene Family; Northern; Rats; Sequence Homology; Western
The expression of the rat cytochrome P450 CYP4 family was studied in hepatic tumors. In most of the primary and transplantable hepatic tumors studied, lauric acid omega-hydroxylase activity associated with the CYP4A subfamily enzymes decreased. The expression of CYP4A proteins and mRNAs in these tumors as assessed by Western and Northern blot was undetectable. However, while RNA analysis revealed the absence of 4A1, 4A2, and 4A3 mRNAs, the expression of CYP4 gene(s) was detected. A Uni-ZAP cDNA library was constructed from a
Chen L; Hardwick J P
Archives of biochemistry and biophysics
1993
1993-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1006/abbi.1993.1003" target="_blank" rel="noreferrer noopener">10.1006/abbi.1993.1003</a>