MicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice

Horie, Takahiro; Nishino, Tomohiro; Baba, Osamu; Kuwabara, Yasuhide; Nakao, Tetsushi; Nishiga, Masataka; Usami, Shunsuke; Izuhara, Masayasu; Sowa, Naoya; Yahagi, Naoya; Shimano, Hitoshi; Matsumura, Shigenobu; Inoue, Kazuo; Marusawa, Hiroyuki; Nakamura, Tomoyuki; Hasegawa, Koji; Kume, Noriaki; Yokode, Masayuki; Kita, Toru; Kimura, Takeshi; Ono, Koh

doi:10.1038/ncomms3883

Cited by 196 publications

(190 citation statements)

References 46 publications

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“…However, the expression of miR-33a and several target genes were not perturbed in the liver, suggesting that the Srebf2 mutant allele did not disrupt miR-33a expression. Furthermore, the phenotypes of our mice did not recapitulate those of miR-33a-defi cient mice, which manifest hepatic steatosis and are prone to increased body weight on chow and high-fat diets ( 48 ). It is possible that miR-33a production is unaffected by our gene-trapped alleles or that there are compensatory changes in our mice that serve to maintain transcript levels for miR-33a target genes.…”

Section: Discussionmentioning

confidence: 81%

SREBP-2-deficient and hypomorphic mice reveal roles for SREBP-2 in embryonic development and SREBP-1c expression

Vergnes

Chin

Vallim

et al. 2016

Journal of Lipid Research

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Cholesterol is a precursor for the biosynthesis of steroid hormones, bile acids, and vitamin D, and is a critical determinant of cell membrane permeability and fl uidity ( 1, 2 ). Cholesterol biosynthesis and homeostasis are regulated by the sterol regulatory element-binding protein (SREBP) transcription factor family. SREBPs are basic-helix-loophelix-leucine zipper transcription factors, which are activated in response to low cellular sterol levels by a series of protein cleavage/transport events ( 3-5 ). There are three SREBP isoforms, which originate from two genes. Srebf1 encodes SREBP-1a and SREBP-1c, which have distinct promoters and 5 ′ exons. Srebf2 encodes SREBP-2. SREBP-1c is the predominant isoform in metabolic tissues such as liver and adipose tissue, but has a relatively weak transcriptionactivation domain compared with the other SREBPs. There is overlap in the activities of the SREBP isoforms, but it is generally held that SREBP-1c primarily targets genes implicated in fatty acid synthesis, whereas SREBP-2 preferentially regulates genes involved in cholesterol synthesis ( 5-8 ). SREBP-1a is a potent activator of both triglyceride and cholesterol biosynthetic pathways, but is expressed at low levels in metabolic tissues, making the physiological role of the protein unclear ( 9 ). SREBP-1c, itself, is regulated by SREBPs, indicating a high degree of cross-talk among SREBP proteins, making it diffi cult to assign distinct physiological functions to individual SREBP proteins.Abstract Cholesterol and fatty acid biosynthesis are regulated by the sterol regulatory element-binding proteins (SREBPs), encoded by Srebf1 and Srebf2 . We generated mice that were either defi cient or hypomorphic for SREBP-2. SREBP-2 defi ciency generally caused death during embryonic development. Analyses of Srebf2؊ / ؊ embryos revealed a requirement for SREBP-2 in limb development and expression of morphogenic genes. We encountered only one viable Srebf2 ؊ / ؊ mouse, which displayed alopecia, attenuated growth, and reduced adipose tissue stores. Hypomorphic SREBP-2 mice (expressing low levels of SREBP-2) survived development, but the female mice exhibited reduced body weight and died between 8 and 12 weeks of age. Male hypomorphic mice were viable but had reduced cholesterol stores in the liver and lower expression of SREBP target genes. Reduced SREBP-2 expression affected SREBP-1 isoforms in a tissue-specifi c manner. In the liver, reduced SREBP-2 expression nearly abolished Srebf1c transcripts and reduced Srebf1a mRNA levels. In contrast, adipose tissue displayed normal expression of SREBP target genes, likely due to a compensatory increase in Srebf1a expression. Our results establish that SREBP-2 is critical for survival and limb patterning during development. Reduced expression of SREBP-2 from the hypomorphic allele leads to early death in females and reduced cholesterol content in the liver, but not in adipose tissue.

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Section: Discussionmentioning

confidence: 81%

SREBP-2-deficient and hypomorphic mice reveal roles for SREBP-2 in embryonic development and SREBP-1c expression

Vergnes

Chin

Vallim

et al. 2016

Journal of Lipid Research

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“…A highly conserved miR, miR-33, is considered a potential therapeutic target for atherosclerosis because recent reports, including ours, [22][23][24][25] indicated that miR-33 has atherogenic effects by reducing high-density lipoprotein cholesterol (HDL-C) levels. 22,23,26,27 MiR-33 (or miR-33a in primates) is encoded by intron 16 of sterol regulatory element-binding factor 2 (SREBF2), a master regulator of sterol and fatty acid synthesis, and suppresses genes involved in cholesterol metabolism, such as ABCA1 and ABCG1 (ATP-binding cassette transporter A1 and G1) as target genes (primates including Homo sapiens also have miR-33b in the intron of SREBF1 in addition to miR-33a 28 ).…”

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confidence: 99%

MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol

Nishiga

Horie

Kuwabara

et al. 2017

Circulation Research

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Rationale: Heart failure and atherosclerosis share the underlying mechanisms of chronic inflammation followed by fibrosis. A highly conserved microRNA (miR), miR-33, is considered as a potential therapeutic target for atherosclerosis because it regulates lipid metabolism and inflammation. However, the role of miR-33 in heart failure remains to be elucidated. Objective: To clarify the role of miR-33 involved in heart failure. Methods and Results: We first investigated the expression levels of miR-33a/b in human cardiac tissue samples with dilated cardiomyopathy. Increased expression of miR-33a was associated with improving hemodynamic parameters. To clarify the role of miR-33 in remodeling hearts, we investigated the responses to pressure overload by transverse aortic constriction in miR-33–deficient (knockout [KO]) mice. When mice were subjected to transverse aortic constriction, miR-33 expression levels were significantly upregulated in wild-type left ventricles. There was no difference in hypertrophic responses between wild-type and miR-33KO hearts, whereas cardiac fibrosis was ameliorated in miR-33KO hearts compared with wild-type hearts. Despite the ameliorated cardiac fibrosis, miR-33KO mice showed impaired systolic function after transverse aortic constriction. We also found that cardiac fibroblasts were mainly responsible for miR-33 expression in the heart. Deficiency of miR-33 impaired cardiac fibroblast proliferation, which was considered to be caused by altered lipid raft cholesterol content. Moreover, cardiac fibroblast–specific miR-33–deficient mice also showed decreased cardiac fibrosis induced by transverse aortic constriction as systemic miR-33KO mice. Conclusion: Our results demonstrate that miR-33 is involved in cardiac remodeling, and it preserves lipid raft cholesterol content in fibroblasts and maintains adaptive fibrotic responses in the remodeling heart.

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“…This gene trap is also likely advantageous in that no region of the Srebf2 locus has been deleted to generate the null (or hypomorphic) alleles, and thus regulatory sequences and other important genes are less likely to be affected unintentionally. This is especially important because engineered mutations could affect the Srebf2 -embedded microRNA gene, miR-33, which represses Srebp1 and cellular cholesterol effl ux 33 ( 3 ).…”

mentioning

confidence: 99%

Srebp2: A master regulator of sterol and fatty acid synthesis

Madison

2016

Journal of Lipid Research

186

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MicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice

Cited by 196 publications

References 46 publications

SREBP-2-deficient and hypomorphic mice reveal roles for SREBP-2 in embryonic development and SREBP-1c expression

SREBP-2-deficient and hypomorphic mice reveal roles for SREBP-2 in embryonic development and SREBP-1c expression

MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol

Srebp2: A master regulator of sterol and fatty acid synthesis

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