Carbohydrate response element binding protein gene expression is positively regulated by thyroid hormone

Area of Science:

• Molecular endocrinology
• Hepatic metabolism
• Gene regulation

Background:

• Thyroid hormone (TH) plays a crucial role in regulating metabolism, but its precise effects on hepatic fatty acid metabolism are not fully understood.
• Carbohydrate response element-binding protein (ChREBP) and sterol response element-binding protein (SREBP)-1c are key regulators of hepatic lipogenesis.
• Both ChREBP and SREBP-1c are target genes of liver X receptors (LXRs), which are known to interact with thyroid hormone receptors (TRs).

Purpose of the Study:

• To investigate whether thyroid hormone receptors (TRs) regulate the expression of the mouse ChREBP gene.
• To elucidate the molecular mechanism by which TH influences hepatic lipogenesis through ChREBP regulation.

Main Methods:

• Quantitative analysis of ChREBP mRNA and protein expression in mouse liver.
• Run-on assays and luciferase reporter assays to assess gene transcription.
• Electrophoretic mobility shift assays (EMSAs) to determine protein-DNA interactions.
• Site-directed mutagenesis of the ChREBP gene promoter.

Main Results:

• TH significantly up-regulated both ChREBP mRNA and protein levels in mouse liver.
• TH and TR-beta1 were found to positively regulate ChREBP gene transcription.
• TR-beta1 specifically binds to the LXRE2 site on the ChREBP promoter, which is critical for TH-mediated transcriptional regulation.
• TH also enhanced human ChREBP gene expression and promoter activity.

Conclusions:

• Thyroid hormone positively regulates ChREBP gene expression at the transcriptional level in mammals, mediated by TR-beta1.
• This study identifies a novel mechanism where TH fine-tunes hepatic lipogenesis by reciprocally regulating SREBP-1c and ChREBP gene expression.