Abstract
To investigate the mechanisms controlling tissue-specific expression of the human apolipoprotein (apo) E/C-I gene locus, human apoE and apoC-I gene constructs containing various lengths of the 5'-flanking or 3'-flanking region were used to create transgenic mice. Several essential tissue-specific regulatory elements were identified in the region between the apoE and the apoC-I genes, as well as in a distal domain found downstream of the apoC-I gene. Most notably, transcription of both the apoE and apoC-I genes in the liver, their major site of expression, required downstream regulatory elements, possibly located within a common regulatory domain more than 2 kilobases 3' of the apoC-I gene (about 14 kilobases downstream of the apoE gene promoter). In the region between the apoE and apoC-I genes, a single strong positive element directed apoE and apoC-I gene expression in the skin. The intergenic region also contained elements that stimulated apoE gene expression in the brain and silenced apoE gene expression only in the kidney. These results demonstrate that multiple independent regulatory elements control expression of the human apoE/C-I gene locus in various tissues. Transgenic mice expressing human apoC-I in the liver exhibited plasma triglyceride levels that were 2-3-fold higher than those in control mice, an effect not found when transgenic human apoE was produced. This result suggests that apoC-I may modulate the metabolism of triglyceride-rich lipoproteins.
Highlights
To investigate the mechanisms controlling tissuespecific expression of the human apolipoprotein E/C-I gene locus, human apoE and apoC-I gene constructs containing various lengths of the 5”flanking or 3”flanking region were used to create transgenic mice
While the expression of most apolipoproteins is restricted primarily to the liver and intestine [6, 7], apoE is expressed in a wide distribution of tissues
Apolipoprotein E is produced by specific cell types in several peripheral tissues [9,10,11,12,13,14,15], perhaps reflecting local metabolic requirements
Summary
Observed for the HEGl and HESHl constructs (highkidney Transgenic mice harboring either of the two apoC-I conexpression, low testis and brain expression) compared with structswiththe longest 5”flanking sequence (CI.361 and the CI.361 construct (highliver expression, moderatekidney, CI.EB) expressed apoC-I mRNA a t noticeably higher levels skin, and brainexpression) suggested that important regula- in the skin These resuwltesre in agreementwith the previous tory elements controlling apoE gene expression were located findings with HE54.4 apoE transgenic mice, suggesting that more than 1.7 kb downstream of the apoEgene [22]. Extendingthe3”flanking sequence from 1.7 to 4.0 kb apoC-I gene, this elementwould have to directhigh levels of downstream (HE54.4) had a marked effect on the pattern of hepatic apoE gene expression without affecting apoC-I gene apoE gene expression in different tissues: apoE expression in expression in the liver Because this possibility seems quite the kidney was silenced, and the skin hada high amount of unlikely, we propose that the downstream region controlling human apoE mRNA.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
