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

Xiaoyue Pan, Yuxia Zhang, Li Wang, M. Mahmood Hussain*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

159 Citations (Scopus)

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 languageEnglish
Pages (from-to)174-186
Number of pages13
JournalCell Metabolism
Volume12
Issue number2
DOIs
Publication statusPublished - 4 Aug 2010
Externally publishedYes

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