Regulation of hepatic lipogenesis by the zinc finger protein Zbtb20

Nat Commun. 2017 Mar 22:8:14824. doi: 10.1038/ncomms14824.

Abstract

Hepatic de novo lipogenesis (DNL) converts carbohydrates into triglycerides and is known to influence systemic lipid homoeostasis. Here, we demonstrate that the zinc finger protein Zbtb20 is required for DNL. Mice lacking Zbtb20 in the liver exhibit hypolipidemia and reduced levels of liver triglycerides, along with impaired hepatic lipogenesis. The expression of genes involved in glycolysis and DNL, including that of two ChREBP isoforms, is decreased in livers of knockout mice. Zbtb20 binds to and enhances the activity of the ChREBP-α promoter, suggesting that altered metabolic gene expression is mainly driven by ChREBP. In addition, ChREBP-β overexpression largely restores hepatic expression of genes involved in glucose and lipid metabolism, and increases plasma and liver triglyceride levels in knockout mice. Finally, we show that Zbtb20 ablation protects from diet-induced liver steatosis and improves hepatic insulin resistance. We suggest ZBTB20 is an essential regulator of hepatic lipogenesis and may be a therapeutic target for the treatment of fatty liver disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Carbohydrates / chemistry
  • Cell Nucleus / metabolism
  • Dietary Carbohydrates
  • Fatty Liver / genetics
  • Fatty Liver / pathology
  • Gene Deletion
  • Gene Expression Regulation
  • Glucose / metabolism
  • Glycolysis
  • Homeostasis
  • Humans
  • Insulin Resistance
  • Lipogenesis* / genetics
  • Liver / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Proteins / metabolism
  • Protein Transport
  • Transcription Factors / deficiency
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Triglycerides / blood
  • Triglycerides / metabolism

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Carbohydrates
  • Dietary Carbohydrates
  • Mlxipl protein, mouse
  • Nuclear Proteins
  • Transcription Factors
  • Triglycerides
  • Zbtb20 protein, mouse
  • Glucose