Role of 11β-hydroxysteroid dehydrogenase type 1 in liver fibrosis and inflammation in non-alcoholic fatty liver disease
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Date
05/07/2014Item status
Restricted AccessEmbargo end date
31/12/2100Author
Zou, Xiantong
Metadata
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.