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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). Mttp is regulated by carbohydrate response element binding protein (ChREBP) and small heterodimer partner (SHP). However, it is unclear whether both coordinately regulate Mttp expression and VLDL secretion. Here, adenoviral overexpression of ChREBP and SHP in rat primary hepatocytes induced and suppressed Mttp mRNA, respectively. However, Mttp induction by ChREBP was much more potent than suppression by SHP. Promoter assays of Mttp and the liver type pyruvate kinase gene revealed that SHP and ChREBP did not affect the transcriptional activity of each other. Mttp 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.

Carbohydrate response element binding protein (ChREBP) and peroxisome proliferator-activated receptor alpha (PPARα) play an important role in the regulation of lipid metabolism in the liver. Chrebp and Ppara mRNA levels are equally abundant in brown adipose tissue and liver. However, their functions in brown adipose tissues are unclear. In this study, we attempted to clarify the role of ChREBP and PPARα using brown adipose HB2 cell lines and tissues from wild type and Chrebp-/- C57BL/6J mice. In liver and brown adipose tissues, Chrebpb mRNA levels in the fasting state were much lower than those fed ad libitum, while Ppara mRNA levels in the fasting state were much higher than in the fed state. In differentiated brown adipose HB2 cell lines, glucose increased mRNA levels of ChREBP target genes such as Chrebpb, Fasn, and Glut4 in a dose dependent manner, while glucose decreased both Chrebpa and Ppara mRNA levels. Accordingly, adenoviral overexpression of ChREBP and a reporter assay demonstrated that ChREBP partially suppressed Ppara and Acox mRNA expression. Moreover, in brown adipose tissues from Chrebp-/- mice, Chrebpb and Fasn mRNA levels in the ad libitum fed state were much lower than those in the fasting state, while Ppara and Acox mRNA levels were not. Finally, using Wy14,643, a selective PPARα agonist, and overexpression of PPARα partially suppressed glucose induction of Chrebpb and Fasn mRNA in HB2 cells. In conclusion, the feedback loop between ChREBP and PPARα plays an important role in the regulation of lipogenesis in brown adipocytes.