Abstract
We examined the role of clock genes in the diurnal regulation of plasma triglyceride-rich apolipoprotein B-lipoproteins and their biosynthetic chaperone, microsomal triglyceride transfer protein (MTP). Clockmt/mt mice showed sustained hypertriglyceridemia and high MTP expression. CLOCK knockdown activated MTP promoter and reduced small heterodimer partner (SHP, NROB2). CLOCK upregulated SHP by binding to its E box. SHP suppressed MTP expression by binding to the HNF47alpha;/LRH-1 at the MTP promoter. Cyclic expression of MTP after serum shock was abrogated by siCLOCK and siSHP. Plasma triglyceride and MTP showed reduced diurnal variations in Shp-/- mice. Whereas peaks and nadirs in SHP expression were inversely correlated with those of MTP, these changes were reduced in Clockmt/mt mice. Expression of Shp abrogated hypertriglyceridemia in Clockmt/mt mice. Together, these studies describe a role of Clock/Shp in the diurnal regulation of MTP and plasma triglyceride and indicate that disruptions in circadian regulation might cause hyperlipidemia.
Original language | English |
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Pages (from-to) | 174-186 |
Number of pages | 13 |
Journal | Cell Metabolism |
Volume | 12 |
Issue number | 2 |
DOIs | |
Publication status | Published - 4 Aug 2010 |
Externally published | Yes |