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 journalArticlepeer-review

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.

Original languageEnglish
Article number109506
JournalCell Reports
Volume36
Issue number6
DOIs
Publication statusPublished - 2021 Aug 10

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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