ChREBP Rather Than SHP Regulates Hepatic VLDL Secretion

Abstract

The regulation of hepatic very-low-density lipoprotein (VLDL) secretion plays an important role in the pathogenesis of dyslipidemia and fatty liver diseases. VLDL is controlled by hepatic microsomal triglyceride transfer protein (MTTP). <i>Mttp</i> is regulated by carbohydrate response element binding protein (ChREBP) and small heterodimer partner (SHP). However, it is unclear whether both coordinately regulate <i>Mttp</i> expression and VLDL secretion. Here, adenoviral overexpression of ChREBP and SHP in rat primary hepatocytes induced and suppressed <i>Mttp</i> mRNA, respectively. However, <i>Mttp</i> induction by ChREBP was much more potent than suppression by SHP. Promoter assays of <i>Mttp</i> and the liver type pyruvate kinase gene revealed that SHP and ChREBP did not affect the transcriptional activity of each other. <i>Mttp</i> mRNA and protein levels of Shp^-/- mice were similar to those of wild-types; however, those of Chrebp^-/-Shp^-/- and Chrebp^-/- mice were significantly much lower. Consistent with this, the VLDL particle number and VLDL secretion rates in Shp^-/- mice were similar to wild-types but were much lower in Chrebp^-/- and Chrebp^-/-Shp^-/- mice. These findings suggest that ChREBP, rather than SHP, regulates VLDL secretion under normal conditions and that ChREBP and SHP do not affect the transcriptional activities of each other.