[PDF][PDF] Diurnal regulation of MTP and plasma triglyceride by CLOCK is mediated by SHP

X Pan, Y Zhang, L Wang, MM Hussain - Cell metabolism, 2010 - cell.com
Cell metabolism, 2010cell.com
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). Clock mt/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 HNF4α/LRH-1 at the MTP promoter. Cyclic …
Summary
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 HNF4α/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.
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