ChREBP Rather Than SHP Regulates Hepatic VLDL Secretion

Area of Science:

• Biochemistry
• Molecular Biology
• Metabolic Diseases

Background:

• Hepatic very-low-density lipoprotein (VLDL) secretion is crucial in lipid metabolism and linked to dyslipidemia and fatty liver.
• Microsomal triglyceride transfer protein (MTTP) controls VLDL production.
• Carbohydrate response element binding protein (ChREBP) and small heterodimer partner (SHP) are known regulators of Mttp.

Purpose of the Study:

• To investigate the distinct and coordinated roles of ChREBP and SHP in regulating Mttp expression and VLDL secretion.
• To determine the primary regulator of VLDL secretion between ChREBP and SHP.

Main Methods:

• Adenoviral overexpression of ChREBP and SHP in rat primary hepatocytes.
• Analysis of Mttp mRNA and protein levels in wild-type, Shp knockout, Chrebp knockout, and combined knockout mice.
• Assessment of VLDL particle number and secretion rates in these mouse models.
• Reporter assays to evaluate the transcriptional activity of Mttp and liver pyruvate kinase genes.

Main Results:

• ChREBP robustly induced Mttp mRNA, while SHP suppressed it, with ChREBP's effect being more potent.
• SHP and ChREBP did not influence each other's transcriptional activity on Mttp or liver pyruvate kinase.
• Mttp expression and VLDL secretion were significantly reduced in Chrebp knockout mice (with or without SHP), but not in Shp knockout mice compared to wild-types.

Conclusions:

• ChREBP is the predominant regulator of hepatic Mttp expression and VLDL secretion under normal physiological conditions.
• SHP plays a minor or negligible role in regulating VLDL secretion compared to ChREBP.
• The transcriptional activities of ChREBP and SHP on Mttp are independent.