The E-box-like sterol regulatory element mediates the insulin-stimulated expression of hepatic clusterin.
Clusterin (also known as apolipoprotein J) is a highly conserved glycoprotein involved in various biological processes, including attenuation of complement activity, sperm maturation, apoptosis, and reverse lipid transport. Although clusterin is reportedly associated with metabolic diseases, the metabolic regulation of clusterin expression is largely unknown. We investigated the effect of insulin on hepatic clusterin expression and its underlying mechanisms. Insulin increased the mRNA and protein levels of clusterin in primary hepatocytes and hepatoma cell lines. Serial deletion and mutant analysis of the clusterin promoter demonstrated that insulin-stimulated transactivation is mediated via a non-canonical E-box (NCE-box) motif in the proximal upstream region. Interestingly, sterol regulatory element binding protein-1c (SREBP-1c) co-transfection showed the same transactivation pattern as insulin stimulation in serial deletion and mutant promoter analysis. In contrast, co-transfection with a dominant negative form of SREBP-1c inhibited insulin-stimulated clusterin expression. Furthermore, insulin increased the recruitment of SREBP-1c to the NCE-box of the clusterin promoter region. Taken together, our results suggest that an NCE-box within the clusterin promoter is necessary for insulin-stimulated hepatic expression of clusterin via SREBP-1c.
Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea; Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Gyun-Sik
GS
Oh
Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Gukhan
G
Kim
Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea; Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Jin
J
Yoon
Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
Geun Hyang
GH
Kim
Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea; Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea. Electronic address: swkim7@amc.seoul.kr.
Seung-Whan
SW
Kim
D000818:Animals; D002478:Cells, Cultured; D051152:Clusterin / Q000235:genetics / Q000378:metabolism*; D024721:E-Box Elements / Q000235:genetics*; D022781:Hepatocytes / Q000502:physiology*; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics* / Q000378:metabolism*
D051152:Clusterin; D007328:Insulin; D051780:Sterol Regulatory Element Binding Protein 1
Apolipoprotein J; Clusterin; Insulin; Non-canonical E-box; Sterol regulatory element binding protein-1c