Feedback repression of PPARα signaling by Let-7 microRNA

Tomoki Yagai; Tingting Yan; Yuhong Luo; Shogo Takahashi; Daisuke Aibara; Donghwan Kim; Chad N. Brocker; Moshe Levi; Hozumi Motohashi; Frank J. Gonzalez

doi:10.1016/j.celrep.2021.109506

Feedback repression of PPARα signaling by Let-7 microRNA

Tomoki Yagai, Tingting Yan, Yuhong Luo, Shogo Takahashi, Daisuke Aibara, Donghwan Kim, Chad N. Brocker, Moshe Levi, Hozumi Motohashi, Frank J. Gonzalez

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

Abstract

Peroxisome proliferator-activated receptor α (PPARα) controls hepatic lipid homeostasis and is the target of lipid-lowering fibrate drugs. PPARα activation represses expression of let-7 microRNA (miRNA), but the function of let-7 in PPARα signaling and lipid metabolism is unknown. In the current study, a hepatocyte-specific let-7b/c2 knockout (let7b/c2^ΔHep) mouse line is generated, and these mice are found to exhibit pronounced resistance to diet-induced obesity and fatty liver. Let-7 inhibition by hepatocyte-specific let-7 sponge expression shows similar phenotypes as let7b/c2^ΔHep mice. RNA sequencing (RNA-seq) analysis reveals that hepatic PPARα signaling is repressed in let7b/c2^ΔHep mice. Protein expression of the obligate PPARα heterodimer partner retinoid X receptor α (RXRα) is reduced in the livers of let7b/c2^ΔHep mice. Ring finger protein 8 (Rnf8), which is a direct target of let-7, is elevated in let7b/c2^ΔHep mouse liver and identified as a E3 ubiquitin ligase for RXRα. This study highlights a let-7-RNF8-RXRα regulatory axis that modulates hepatic lipid catabolism.

Original language	English
Article number	109506
Journal	Cell Reports
Volume	36
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2021.109506
Publication status	Published - 2021 Aug 10
Externally published	Yes

Keywords

PPARα
RNF8
RXRα
fatty liver disease
let-7
nuclear receptors
obesity
ubiquitin-proteasome system

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2021.109506

Cite this

@article{f69b8cfd2bb8423d9faab69b53e692c5,

title = "Feedback repression of PPARα signaling by Let-7 microRNA",

abstract = "Peroxisome proliferator-activated receptor α (PPARα) controls hepatic lipid homeostasis and is the target of lipid-lowering fibrate drugs. PPARα activation represses expression of let-7 microRNA (miRNA), but the function of let-7 in PPARα signaling and lipid metabolism is unknown. In the current study, a hepatocyte-specific let-7b/c2 knockout (let7b/c2ΔHep) mouse line is generated, and these mice are found to exhibit pronounced resistance to diet-induced obesity and fatty liver. Let-7 inhibition by hepatocyte-specific let-7 sponge expression shows similar phenotypes as let7b/c2ΔHep mice. RNA sequencing (RNA-seq) analysis reveals that hepatic PPARα signaling is repressed in let7b/c2ΔHep mice. Protein expression of the obligate PPARα heterodimer partner retinoid X receptor α (RXRα) is reduced in the livers of let7b/c2ΔHep mice. Ring finger protein 8 (Rnf8), which is a direct target of let-7, is elevated in let7b/c2ΔHep mouse liver and identified as a E3 ubiquitin ligase for RXRα. This study highlights a let-7-RNF8-RXRα regulatory axis that modulates hepatic lipid catabolism.",

keywords = "PPARα, RNF8, RXRα, fatty liver disease, let-7, nuclear receptors, obesity, ubiquitin-proteasome system",

author = "Tomoki Yagai and Tingting Yan and Yuhong Luo and Shogo Takahashi and Daisuke Aibara and Donghwan Kim and Brocker, {Chad N.} and Moshe Levi and Hozumi Motohashi and Gonzalez, {Frank J.}",

note = "Funding Information: We thank Linda G. Byrd for assistance with the mouse studies and Oksana Gavrilova for mouse body composition analysis. This work was funded by the National Cancer Institute Intramural Research Program . T. Yagai and S. Takahashi were supported in part by a fellowship from the Japan Society for the Promotion of Science . The funding sponsors had no role in the design, collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. Publisher Copyright: {\textcopyright} 2021",

year = "2021",

month = aug,

day = "10",

doi = "10.1016/j.celrep.2021.109506",

language = "English",

volume = "36",

journal = "Cell Reports",

issn = "2211-1247",

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number = "6",

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TY - JOUR

T1 - Feedback repression of PPARα signaling by Let-7 microRNA

AU - Yagai, Tomoki

AU - Yan, Tingting

AU - Luo, Yuhong

AU - Takahashi, Shogo

AU - Aibara, Daisuke

AU - Kim, Donghwan

AU - Brocker, Chad N.

AU - Levi, Moshe

AU - Motohashi, Hozumi

AU - Gonzalez, Frank J.

N1 - Funding Information: We thank Linda G. Byrd for assistance with the mouse studies and Oksana Gavrilova for mouse body composition analysis. This work was funded by the National Cancer Institute Intramural Research Program . T. Yagai and S. Takahashi were supported in part by a fellowship from the Japan Society for the Promotion of Science . The funding sponsors had no role in the design, collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. Publisher Copyright: © 2021

PY - 2021/8/10

Y1 - 2021/8/10

N2 - Peroxisome proliferator-activated receptor α (PPARα) controls hepatic lipid homeostasis and is the target of lipid-lowering fibrate drugs. PPARα activation represses expression of let-7 microRNA (miRNA), but the function of let-7 in PPARα signaling and lipid metabolism is unknown. In the current study, a hepatocyte-specific let-7b/c2 knockout (let7b/c2ΔHep) mouse line is generated, and these mice are found to exhibit pronounced resistance to diet-induced obesity and fatty liver. Let-7 inhibition by hepatocyte-specific let-7 sponge expression shows similar phenotypes as let7b/c2ΔHep mice. RNA sequencing (RNA-seq) analysis reveals that hepatic PPARα signaling is repressed in let7b/c2ΔHep mice. Protein expression of the obligate PPARα heterodimer partner retinoid X receptor α (RXRα) is reduced in the livers of let7b/c2ΔHep mice. Ring finger protein 8 (Rnf8), which is a direct target of let-7, is elevated in let7b/c2ΔHep mouse liver and identified as a E3 ubiquitin ligase for RXRα. This study highlights a let-7-RNF8-RXRα regulatory axis that modulates hepatic lipid catabolism.

AB - Peroxisome proliferator-activated receptor α (PPARα) controls hepatic lipid homeostasis and is the target of lipid-lowering fibrate drugs. PPARα activation represses expression of let-7 microRNA (miRNA), but the function of let-7 in PPARα signaling and lipid metabolism is unknown. In the current study, a hepatocyte-specific let-7b/c2 knockout (let7b/c2ΔHep) mouse line is generated, and these mice are found to exhibit pronounced resistance to diet-induced obesity and fatty liver. Let-7 inhibition by hepatocyte-specific let-7 sponge expression shows similar phenotypes as let7b/c2ΔHep mice. RNA sequencing (RNA-seq) analysis reveals that hepatic PPARα signaling is repressed in let7b/c2ΔHep mice. Protein expression of the obligate PPARα heterodimer partner retinoid X receptor α (RXRα) is reduced in the livers of let7b/c2ΔHep mice. Ring finger protein 8 (Rnf8), which is a direct target of let-7, is elevated in let7b/c2ΔHep mouse liver and identified as a E3 ubiquitin ligase for RXRα. This study highlights a let-7-RNF8-RXRα regulatory axis that modulates hepatic lipid catabolism.

KW - PPARα

KW - RNF8

KW - RXRα

KW - fatty liver disease

KW - let-7

KW - nuclear receptors

KW - obesity

KW - ubiquitin-proteasome system

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U2 - 10.1016/j.celrep.2021.109506

DO - 10.1016/j.celrep.2021.109506

M3 - Article

C2 - 34380035

AN - SCOPUS:85112180584

SN - 2211-1247

VL - 36

JO - Cell Reports

JF - Cell Reports

IS - 6

M1 - 109506

ER -

Feedback repression of PPARα signaling by Let-7 microRNA

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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