Unravelling the role of AKR1D1 in human hepatocytes
Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and is rapidly becoming one of the leading indications for liver transplantation worldwide. The cellular processes and molecular targets that govern disease development and progression remain to be fully...
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ndltd-bl.uk-oai-ethos.bl.uk-7361092018-05-12T03:28:55ZUnravelling the role of AKR1D1 in human hepatocytesNikolaou, NikolaosHodson, Leanne ; Tomlinson, Jeremy W.2017Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and is rapidly becoming one of the leading indications for liver transplantation worldwide. The cellular processes and molecular targets that govern disease development and progression remain to be fully defined and currently there are no licensed treatments. Steroid 5β-reductase (AKR1D1) is highly expressed in human liver where it inactivates steroid hormones and catalyses a fundamental step in bile acid synthesis. I have hypothesised that AKR1D1 plays a crucial regulatory role in hepatic metabolic homeostasis. In human hepatoma cell lines, genetic manipulation of AKR1D1 altered primary bile acid biosynthesis and steroid hormone action. Furthermore, gene silencing of AKR1D1 increased hepatocyte triglyceride accumulation through increased de novo lipogenesis and decreased β- oxidation, fueling hepatocyte inflammation as well as increasing glycogen synthesis. I have shown that AKR1D1 has a potent ability to regulate the metabolic phenotype of human hepatocytes suggesting a crucial role in the pathophysiology of NAFLD.University of Oxfordhttp://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.736109https://ora.ox.ac.uk/objects/uuid:c224fa03-040d-447e-9d25-ab268da26274Electronic Thesis or Dissertation |
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Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and is rapidly becoming one of the leading indications for liver transplantation worldwide. The cellular processes and molecular targets that govern disease development and progression remain to be fully defined and currently there are no licensed treatments. Steroid 5β-reductase (AKR1D1) is highly expressed in human liver where it inactivates steroid hormones and catalyses a fundamental step in bile acid synthesis. I have hypothesised that AKR1D1 plays a crucial regulatory role in hepatic metabolic homeostasis. In human hepatoma cell lines, genetic manipulation of AKR1D1 altered primary bile acid biosynthesis and steroid hormone action. Furthermore, gene silencing of AKR1D1 increased hepatocyte triglyceride accumulation through increased de novo lipogenesis and decreased β- oxidation, fueling hepatocyte inflammation as well as increasing glycogen synthesis. I have shown that AKR1D1 has a potent ability to regulate the metabolic phenotype of human hepatocytes suggesting a crucial role in the pathophysiology of NAFLD. |
author2 |
Hodson, Leanne ; Tomlinson, Jeremy W. |
author_facet |
Hodson, Leanne ; Tomlinson, Jeremy W. Nikolaou, Nikolaos |
author |
Nikolaou, Nikolaos |
spellingShingle |
Nikolaou, Nikolaos Unravelling the role of AKR1D1 in human hepatocytes |
author_sort |
Nikolaou, Nikolaos |
title |
Unravelling the role of AKR1D1 in human hepatocytes |
title_short |
Unravelling the role of AKR1D1 in human hepatocytes |
title_full |
Unravelling the role of AKR1D1 in human hepatocytes |
title_fullStr |
Unravelling the role of AKR1D1 in human hepatocytes |
title_full_unstemmed |
Unravelling the role of AKR1D1 in human hepatocytes |
title_sort |
unravelling the role of akr1d1 in human hepatocytes |
publisher |
University of Oxford |
publishDate |
2017 |
url |
http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.736109 |
work_keys_str_mv |
AT nikolaounikolaos unravellingtheroleofakr1d1inhumanhepatocytes |
_version_ |
1718638143009193984 |