Chemical investigations into the physiology of bile acid skeletons
| Main Author: | |
|---|---|
| Language: | English |
| Published: |
Case Western Reserve University School of Graduate Studies / OhioLINK
2013
|
| Subjects: | |
| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=case1354810854 |
| id |
ndltd-OhioLink-oai-etd.ohiolink.edu-case1354810854 |
|---|---|
| record_format |
oai_dc |
| spelling |
ndltd-OhioLink-oai-etd.ohiolink.edu-case13548108542021-08-03T05:19:44Z Chemical investigations into the physiology of bile acid skeletons li, qingjiang Chemistry Bile acids are a class of surfactants that facilitate the digestion of dietary lipids and fat soluble vitamins in the intestines of vertebrates. Since they are the end products of cholesterol metabolism, bile acids biosynthesis is the major pathway to remove excess of cholesterol, which is another major biologic role of bile acids. A recycling process called enterohepatic circulation increases the efficiency of bile acid usage during digestion and meanwhile, by reabsorption of bile acids modified by colon bacteria, increases the structural diversity of bile acids in vertebrates. While most of bile acid structural variations occur on the appendages, one variation, the 5¿¿ versus 5¿¿ A/B ring junction, is on the core skeleton. The cause of this variation on the skeleton is especially intriguing considering bile acid is the only major human steroid family bearing 5¿¿ A/B ring junction. Further, a clear trend was found correlating bile acid skeletal variation to the evolution of vertebrates. In this thesis, we discuss our preliminary research on the evolutionary significance of the skeleton in several aspects of bile acid functions. First, three 5¿¿ bile acids were synthesized using the classic strategy of epimerizing ¿¿-carbon of hydroxyl group. This methodology features a shorter synthetic route and better overall yield compared to previous reports with the same synthetic targets. Consequently, after a comprehensive analysis of the detergent properties of 5¿¿ and 5¿¿ bile acids using isothermal titration calorimetry, a conclusion that 5¿¿ bile acids are superior to 5¿¿ bile acids as detergents was drawn in consistent with the hypothesis of bile acids skeleton evolution in vertebrates. The skeletal significance in bile acid cytotoxicity was evaluated by induction of apoptosis to colon cancer cells using flow cytometry and confocal microscopy. The results were complicated by a recovery mechanism of bile acid induced apoptosis and did not correlate to bile acid evolution. The investigation of bile acids’ ability to traverse cellular membranes was undertaken using radioactively labeled of bile acids. A new methodology for ¿¿,¿¿-unsaturation of the side chain of bile acids was developed and the mechanism of the key step, dehydrogenation by selenium dioxide, was thoroughly studied. Isotopic labeling experiments will be performed in the future and the radioactive bile acids with different skeletons will be sent to Wake Forest University for membrane penetration assay. 2013-03-08 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1354810854 http://rave.ohiolink.edu/etdc/view?acc_num=case1354810854 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Chemistry |
| spellingShingle |
Chemistry li, qingjiang Chemical investigations into the physiology of bile acid skeletons |
| author |
li, qingjiang |
| author_facet |
li, qingjiang |
| author_sort |
li, qingjiang |
| title |
Chemical investigations into the physiology of bile acid skeletons |
| title_short |
Chemical investigations into the physiology of bile acid skeletons |
| title_full |
Chemical investigations into the physiology of bile acid skeletons |
| title_fullStr |
Chemical investigations into the physiology of bile acid skeletons |
| title_full_unstemmed |
Chemical investigations into the physiology of bile acid skeletons |
| title_sort |
chemical investigations into the physiology of bile acid skeletons |
| publisher |
Case Western Reserve University School of Graduate Studies / OhioLINK |
| publishDate |
2013 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=case1354810854 |
| work_keys_str_mv |
AT liqingjiang chemicalinvestigationsintothephysiologyofbileacidskeletons |
| _version_ |
1719418576633331712 |