RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network

Kyeongkyu Kim; Kyungjin Boo; Young Suk Yu; Se Kyu Oh; Hyunkyung Kim; Yoon Jeon; Jinhyuk Bhin; Daehee Hwang; Keun Il Kim; Jun Su Lee; Seung Soon Im; Seul Gi Yoon; Il Yong Kim; Je Kyung Seong; Ho Lee; Sungsoon Fang; Sung Hee Baek

doi:10.1038/s41467-017-00215-1

RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network

Kyeongkyu Kim, Kyungjin Boo, Young Suk Yu, Se Kyu Oh, Hyunkyung Kim, Yoon Jeon, Jinhyuk Bhin, Daehee Hwang, Keun Il Kim, Jun Su Lee, Seung Soon Im, Seul Gi Yoon, Il Yong Kim, Je Kyung Seong, Ho Lee, Sungsoon Fang, Sung Hee Baek

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

70 Citations (Scopus)

Abstract

The retinoic acid receptor-related orphan receptor-α (RORα) is an important regulator of various biological processes, including cerebellum development, circadian rhythm and cancer. Here, we show that hepatic RORα controls lipid homeostasis by negatively regulating transcriptional activity of peroxisome proliferators-activated receptor-γ (PPARγ) that mediates hepatic lipid metabolism. Liver-specific Rorα-deficient mice develop hepatic steatosis, obesity and insulin resistance when challenged with a high-fat diet (HFD). Global transcriptome analysis reveals that liver-specific deletion of Rorα leads to the dysregulation of PPARγ signaling and increases hepatic glucose and lipid metabolism. RORα specifically binds and recruits histone deacetylase 3 (HDAC3) to PPARγ target promoters for the transcriptional repression of PPARγ. PPARγ antagonism restores metabolic homeostasis in HFD-fed liver-specific Rorα deficient mice. Our data indicate that RORα has a pivotal role in the regulation of hepatic lipid homeostasis. Therapeutic strategies designed to modulate RORα activity may be beneficial for the treatment of metabolic disorders.

Original language	English
Article number	162
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00215-1
Publication status	Published - 2017 Dec 1
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

UN SDGs

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

Access to Document

10.1038/s41467-017-00215-1

Cite this

Kim, K., Boo, K., Yu, Y. S., Oh, S. K., Kim, H., Jeon, Y., Bhin, J., Hwang, D., Kim, K. I., Lee, J. S., Im, S. S., Yoon, S. G., Kim, I. Y., Seong, J. K., Lee, H., Fang, S., & Baek, S. H. (2017). RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network. Nature communications, 8(1), [162]. https://doi.org/10.1038/s41467-017-00215-1

@article{cff9d0afeed44e3fb81792d65eb91ac2,

title = "RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network",

abstract = "The retinoic acid receptor-related orphan receptor-α (RORα) is an important regulator of various biological processes, including cerebellum development, circadian rhythm and cancer. Here, we show that hepatic RORα controls lipid homeostasis by negatively regulating transcriptional activity of peroxisome proliferators-activated receptor-γ (PPARγ) that mediates hepatic lipid metabolism. Liver-specific Rorα-deficient mice develop hepatic steatosis, obesity and insulin resistance when challenged with a high-fat diet (HFD). Global transcriptome analysis reveals that liver-specific deletion of Rorα leads to the dysregulation of PPARγ signaling and increases hepatic glucose and lipid metabolism. RORα specifically binds and recruits histone deacetylase 3 (HDAC3) to PPARγ target promoters for the transcriptional repression of PPARγ. PPARγ antagonism restores metabolic homeostasis in HFD-fed liver-specific Rorα deficient mice. Our data indicate that RORα has a pivotal role in the regulation of hepatic lipid homeostasis. Therapeutic strategies designed to modulate RORα activity may be beneficial for the treatment of metabolic disorders.",

author = "Kyeongkyu Kim and Kyungjin Boo and Yu, {Young Suk} and Oh, {Se Kyu} and Hyunkyung Kim and Yoon Jeon and Jinhyuk Bhin and Daehee Hwang and Kim, {Keun Il} and Lee, {Jun Su} and Im, {Seung Soon} and Yoon, {Seul Gi} and Kim, {Il Yong} and Seong, {Je Kyung} and Ho Lee and Sungsoon Fang and Baek, {Sung Hee}",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41467-017-00215-1",

language = "English",

volume = "8",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network

AU - Kim, Kyeongkyu

AU - Boo, Kyungjin

AU - Yu, Young Suk

AU - Oh, Se Kyu

AU - Kim, Hyunkyung

AU - Jeon, Yoon

AU - Bhin, Jinhyuk

AU - Hwang, Daehee

AU - Kim, Keun Il

AU - Lee, Jun Su

AU - Im, Seung Soon

AU - Yoon, Seul Gi

AU - Kim, Il Yong

AU - Seong, Je Kyung

AU - Lee, Ho

AU - Fang, Sungsoon

AU - Baek, Sung Hee

PY - 2017/12/1

Y1 - 2017/12/1

N2 - The retinoic acid receptor-related orphan receptor-α (RORα) is an important regulator of various biological processes, including cerebellum development, circadian rhythm and cancer. Here, we show that hepatic RORα controls lipid homeostasis by negatively regulating transcriptional activity of peroxisome proliferators-activated receptor-γ (PPARγ) that mediates hepatic lipid metabolism. Liver-specific Rorα-deficient mice develop hepatic steatosis, obesity and insulin resistance when challenged with a high-fat diet (HFD). Global transcriptome analysis reveals that liver-specific deletion of Rorα leads to the dysregulation of PPARγ signaling and increases hepatic glucose and lipid metabolism. RORα specifically binds and recruits histone deacetylase 3 (HDAC3) to PPARγ target promoters for the transcriptional repression of PPARγ. PPARγ antagonism restores metabolic homeostasis in HFD-fed liver-specific Rorα deficient mice. Our data indicate that RORα has a pivotal role in the regulation of hepatic lipid homeostasis. Therapeutic strategies designed to modulate RORα activity may be beneficial for the treatment of metabolic disorders.

AB - The retinoic acid receptor-related orphan receptor-α (RORα) is an important regulator of various biological processes, including cerebellum development, circadian rhythm and cancer. Here, we show that hepatic RORα controls lipid homeostasis by negatively regulating transcriptional activity of peroxisome proliferators-activated receptor-γ (PPARγ) that mediates hepatic lipid metabolism. Liver-specific Rorα-deficient mice develop hepatic steatosis, obesity and insulin resistance when challenged with a high-fat diet (HFD). Global transcriptome analysis reveals that liver-specific deletion of Rorα leads to the dysregulation of PPARγ signaling and increases hepatic glucose and lipid metabolism. RORα specifically binds and recruits histone deacetylase 3 (HDAC3) to PPARγ target promoters for the transcriptional repression of PPARγ. PPARγ antagonism restores metabolic homeostasis in HFD-fed liver-specific Rorα deficient mice. Our data indicate that RORα has a pivotal role in the regulation of hepatic lipid homeostasis. Therapeutic strategies designed to modulate RORα activity may be beneficial for the treatment of metabolic disorders.

UR - http://www.scopus.com/inward/record.url?scp=85026528725&partnerID=8YFLogxK

U2 - 10.1038/s41467-017-00215-1

DO - 10.1038/s41467-017-00215-1

M3 - Article

C2 - 28757615

AN - SCOPUS:85026528725

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 162

ER -

RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this