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Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance

Lale Ozcan1, Devram S Ghorpade1, Ze Zheng1

  • 1Department of Medicine, Columbia University, New York, NY 10032, USA.

Cell Reports
|May 31, 2016
PubMed

Insights

Obesity disrupts insulin signaling by activating CaMKII in liver cells, which increases DACH1. This protein represses ATF6, worsening insulin resistance. Targeting DACH1 improves insulin signaling in obesity.

Area of Science:

  • Metabolic diseases
  • Molecular biology
  • Cellular signaling

Background:

  • Defective insulin signaling in liver cells (hepatocytes) is central to type 2 diabetes.
  • Obesity-induced activation of calcium/calmodulin-dependent protein kinase II (CaMKII) in hepatocytes disrupts insulin signaling via the PERK-ATF4-TRB3 pathway.
  • Understanding how CaMKII suppresses ATF6 transcription is crucial for addressing this insulin resistance.

Purpose of the Study:

  • To elucidate the molecular mechanism by which CaMKII suppresses ATF6 in hepatocytes.
  • To identify key proteins involved in the obesity-induced insulin resistance pathway.
  • To evaluate potential therapeutic targets for improving insulin signaling in obesity.

Main Methods:

  • Investigated the interaction between CaMKII, histone deacetylase 4 (HDAC4), and the corepressor DACH1 using molecular biology techniques.
  • Assessed the role of DACH1 and nuclear receptor corepressor (NCOR) in repressing Atf6 transcription.
  • Utilized mouse models of obesity and human liver samples to study DACH1 levels.
  • Employed liver-targeted delivery of constitutively nuclear HDAC4 and DACH1 small hairpin RNA (shRNA) in obese mice.

Main Results:

  • CaMKII phosphorylates and inhibits the nuclear translocation of HDAC4.
  • Reduced HDAC4 nuclear presence decreases DACH1 SUMOylation, protecting DACH1 from degradation.
  • Elevated DACH1, along with NCOR, represses Atf6 transcription, activating the PERK-TRB3 pathway.
  • DACH1 levels are increased in the livers of obese mice and humans.
  • Therapeutic interventions (nuclear HDAC4 or DACH1 shRNA) in obese mice improved ATF6 levels, hepatocyte insulin signaling, and metabolic parameters.

Conclusions:

  • DACH1-mediated corepression of Atf6 in hepatocytes links obesity to insulin resistance.
  • The CaMKII-HDAC4-DACH1 axis represents a critical pathway in the development of hepatic insulin resistance.
  • Targeting DACH1 offers a potential strategy for treating obesity-related type 2 diabetes.

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