Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.700019
Title: The role of 11β-hydroxysteroid dehydrogenase type 1 in liver fibrosis and inflammation in non-alcoholic fatty liver disease
Author: Zou, Xiantong
ISNI:       0000 0004 5991 3779
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2014
Availability of Full Text:
Access through EThOS:
Full text unavailable from EThOS. Please try the link below.
Access through Institution:
Abstract:
Non-alcoholic fatty liver disease (NAFLD) is a worldwide health problem which includes steatosis (triglyceride accumulation alone), non-alcoholic steatohepatitis (NASH, with liver inflammation), fibrosis, cirrhosis and hepatocellular carcinoma. Liver fibrosis, which is a reversible response, is the final phase of most chronic liver disease and is characterized by accumulation of extracellular matrix (ECM) from activated hepatic stellate cells (HSCs). Glucocorticoids (GCs) regulate many aspects of metabolism involved in NAFLD. Also, GCs limit HSC activation in vitro. Tissue GC levels are regulated by 11β- hydroxysteroid dehydrogenase-1 (11β-HSD1) which converts inactive 11- dehydrocorticosterone (DHC) into active corticosterone. Previous studies demonstrate that 11β-HSD1 deficiency improves fatty liver in obesity models, but the role of 11β-HSD1 in mechanisms involved in the progression and/or resolution of hepatic injury is largely unknown. I hypothesized that 11β-HSD1 modulates fibrotic and inflammatory responses during hepatic injury and/or the resolution phase. First I sought to address if the levels of 11β-HSD1 during different models of liver injury are dysregulated. In mice, 11β-HSD1 was down-regulated in choline deficient diet (CDD) induced steatosis, methionine and choline deficient diet (MCDD) induced NASH, carbon tetrachloride (CCL4) induced liver fibrosis and thioacetamide (TAA) induced liver fibrosis. In CCL4 injured livers, the down regulation of 11β- HSD1 was observed around the scar area. To test if 11β-HSD1 plays a key role in modulating liver inflammation and fibrosis responses in NAFLD and liver fibrosis I used initially11β-HSD1 knockout (KO) mice. 11β-HSD1 KO showed higher HSC activation only in the High fat feeding model but not in CDD and MCDD models. In the CCL4 injury model, despite reduced hepatocellular injury, 11β-HSD1 KO mice showed enhanced collagen deposition during peak injury and increased fibrotic gene expression during the early resolution phase although unaltered inflammatory markers during both peak injury and resolution. To further dissect cell-specificity on the effect of 11β-HSD1, I repeated the CCL4-injury model using the hepatocyte-specific 11β-HSD1 KO (Alb-HSD1). Alb-HSD1 mice did not show increased susceptibility to fibrosis compared to control littermates suggesting that the 11β- HSD1 possibly modulates fibrotic response by affecting HSC function. To mechanistically address how GCs inhibit HSC activation in vitro I studied the effects of 11β-HSD1 on HSC in vitro. 11β-HSD1 expression was down-regulated during ‘spontaneous’ HSC activation, and 11β-HSD1 deficiency enhanced susceptibility to activation. The GC (11-DHC)’s inhibitory effect on HSC activation was reversed by 11β-HSD1 inhibition. Finally, to address the clinical relevance of 11β-HSD1 in hepatic injury and/or resolution a selective 11β-HSD1 inhibitor, UE2316, was used. UE2316 induced a pro-fibrotic phenotype in ob/ob mice and CCL4-treated C57BL/6 mice, but had no effect when administered only during injury resolution. In conclusion, 11β-HSD1 deficiency causes increased activation of HSCs following diet and chemical injury and promotes liver fibrosis. Effects of 11β-HSD1 inhibitors, which are a potential treatment for metabolic syndrome, are perhaps offset by adverse outcomes in liver.
Supervisor: Walker, Brian ; Iredale, John ; Andrew, Ruth Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.700019  DOI: Not available
Keywords: 11ß-HSD1 ; liver fibrosis ; NAFLD ; Non-alcoholic fatty liver disease
Share: