Diurnal regulation of MTP and plasma triglyceride by CLOCK is mediated by SHP.
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 HNF4alpha/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 Clock(mt/mt) mice. Expression of Shp abrogated hypertriglyceridemia in Clock(mt/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.
Pan
Xiaoyue
X
Department of Cell Biology and Pediatrics, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
Zhang
Yuxia
Y
Wang
Li
L
Hussain
M Mahmood
MM
D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002940:Circadian Rhythm / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood*
D002352:Carrier Proteins; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; C099713:nuclear receptor subfamily 0, group B, member 2; D056926:CLOCK Proteins