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Mbnl1-mediated alternative splicing of circMlxipl regulates Rbbp6-involved ChREBP turnover to inhibit

Yingying Gong1, Meilin Wei2, Xiaopei Cao3

  • 1Department of Geriatrics, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China.

Molecular Medicine (Cambridge, Mass.)
|November 23, 2024
PubMed
Abstract

Insights

This study reveals how Mbnl1 and circMlxipl regulate ChREBP turnover to protect against lipotoxicity in diabetes. Understanding these mechanisms offers new insights into diabetes pathophysiology and potential therapeutic targets.

Area of Science:

  • Molecular Biology
  • Endocrinology
  • Cell Biology

Background:

  • Diabetes mellitus is a global health crisis and a leading cause of mortality worldwide.
  • Understanding the underlying pathophysiology of diabetes is crucial for developing effective treatments.

Purpose of the Study:

  • To elucidate the molecular mechanisms contributing to lipotoxicity-induced beta-cell damage in diabetes.
  • To investigate the roles of circMlxipl, Mbnl1, Rbbp6, Hdac3, and ChREBP in the pathophysiology of diabetes.

Main Methods:

  • Utilized palmitic acid-treated beta-cells and mouse models of type 2 diabetes (db/db and high-fat diet).
  • Employed histological analysis (H&E), molecular detection (IHC, FISH, Western blot, qRT-PCR), cell behavior assays (MTT, EdU, TUNEL, GSIS), and interaction studies (RIP, RNA pull-down, ChIP, luciferase, Co-IP).

Main Results:

  • Downregulation of Mbnl1 and circMlxipl, and upregulation of Hdac3 and ChREBP observed in diabetic conditions.
  • Mbnl1 overexpression protected against palmitic acid-induced beta-cell damage by modulating circMlxipl splicing and suppressing ChREBP.
  • Hdac3 repressed Mbnl1 transcription, and circMlxipl regulated ChREBP expression and Rbbp6-mediated degradation, impacting beta-cell function in vivo.

Conclusions:

  • Mbnl1-mediated alternative splicing of circMlxipl is a key regulator of Rbbp6-involved ChREBP turnover.
  • This regulatory pathway inhibits lipotoxicity-induced beta-cell damage, offering a novel therapeutic target for diabetes.
Keywords:
ChREBPHdac3Lipotoxic β-cellsMbnl1Rbbp6circMlxipl

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