Regulation of non-alcoholic steatohepatitis and hepatic fibrosis development by the bile acid-FXR-FGF19 pathway
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Schumacher, Justin Douglas.
Regulation of non-alcoholic steatohepatitis and hepatic fibrosis development by the bile acid-FXR-FGF19 pathway. Retrieved from
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TitleRegulation of non-alcoholic steatohepatitis and hepatic fibrosis development by the bile acid-FXR-FGF19 pathway
Date Created2018
Other Date2018-10 (degree)
Extent1 online resource (150 pages : illustrations)
DescriptionIntroduction: Activation of the nuclear receptor farnesoid X receptor (FXR) by bile acids (BAs) in the intestine leads to the induction of fibroblast growth factor 19 (FGF19; ortholog of mouse FGF15). In the liver, FGF19 activates fibroblast growth factor receptor 4 (FGFR4) and the obligate co-receptor β-KLOTHO to negatively regulate BA synthesis. Many additional roles of FGF15 and FGF19 aside from regulation of BA homeostasis are now emerging: increasing insulin sensitivity, reducing total body weight, reducing serum lipid levels, decreasing gluconeogenesis while increasing glycogenesis, and enhancing liver regeneration. For this reason, the development of FXR agonists and FGF19 mimetics is currently a hotbed of research within the pharmaceutical industry for the treatment of non-alcoholic steatohepatitis (NASH) and other liver diseases. We therefore sought to determine the mechanisms by which FGF15 and FGF19 affect the development of NASH and hepatic fibrosis.
Methods: To identify the effects of FGF15 and FGF19 on NASH and hepatic fibrosis, three aims were developed. In Aim 1, wild type and FGF15 deficient mice were fed a high fat diet (HFD) for 6 months to induce NASH. In Aim 2, we treated the human hepatic stellate cell (HSC) line LX-2 with recombinant FGF19 to determine if FGF19 can function as a directly acting profibrogenic factor to HSCs. Lastly, in Aim 3, FGF15 deficient and overexpressing mice were fed a diet containing either cholestyramine or cholic acid and treated with chronic carbon tetrachloride (CCl4). The combination of genotypes and diets would lead to the dissociation of BA levels from Fgf15 expression and enable the determination of the BA dependent and independent effects of FGF15 on hepatic fibrosis.
Hypothesis: FGF15 overexpressing transgenic mice were previously shown to have reduced hepatic steatosis and improved insulin sensitivity. Therefore, in Aim 1, we hypthothesized that FGF15 deficiency would worsen all characteristics of NASH; steatosis, inflammation, fibrosis, and metabolic syndrome. FGFR activation by FGFs other than FGF15 and FGF19 has been shown to lead to HSC activation and proliferation. Thus, in Aim 2, we hypothesized that treatment of LX-2 cells with FGF19 would lead to HSC activation and proliferation. FXR activation in HSCs by BAs has been shown to be protective against the development of hepatic fibrosis. Therefore, in Aim 3, we hypothesized that FGF15 would affect CCl4 induced hepatic fibrosis indirectly by regulating total BA pool size and subsequently altering FXR activity in HSCs.
Results: In agreement with our hypothesis, in Aim 1, FGF15 deficiency worsened HFD-induced metabolic syndrome, altered expression of lipid homeostatic genes, and led to a trend for worsened hepatic inflammation. Opposite of our hypothesis, FGF15 deficient mice were protected against the development of fibrosis. In Aim 2, we found that FGF19 can activate FGFR in LX-2 cells. However, contrary to our hypothesis, FGFR activation in LX-2 cells by FGF19 did not affect activation or proliferation. In Aim 3, the combinations of genotype and diet effectively led to multiple combinations of total BA pool sizes and Fgf15 expression. Through these combinations, we were able to determine that FGF15 can affect hepatic inflammation and fibrosis development indirectly via regulation of BA homeostasis and subsequently FXR activity in the liver.
Conclusion: The findings from the three independent but integrated research aims indicate that FGF15 deficiency is protective against the development of hepatic fibrosis. FGF15 and FGF19 do not appear to directly induce HSC activation or proliferation as LX-2 cells were not activated by FGF19 treatment nor did FGF15 overexpression worsen hepatic fibrosis. The mechanism underlying the protective effect of FGF15 deficiency on hepatic fibrosis appears to be dependent upon FGF15 regulation of BA homeostasis and hepatic FXR activity.
NotePh.D.
NoteIncludes bibliographical references
Noteby Justin Douglas Schumacher
Genretheses, ETD doctoral
Languageeng
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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