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- Ellis, Ewa C S
(författare)
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Use of primary human hepatocytes for the elucidation of bile acid synthesis
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the present investigation we cultured primary human hepatocytes on matrigel under serum-free conditions and studied bile acid formation. The following observations were made: · The major steroid products excreted from primary human hepatocytes into the culture medium were cholic acid, CA (70%) and chenodeoxycholic acid, CDCA (25%) conjugated with glycine or taurine. This composition is similar to that formed in man under in vivo conditions. · A new alternative pathway from cholesterol to cholic acid was defined in the hepatocytes including 7alpha, 12alpha, 27-trihydroxy-4-cholesten-3 -one, 7alpha,12alpha-dihydroxy-3-oxo-4-cholestenoic acid and 7alpha,12alpha-dihydroxy-3oxo-5beta-cholanoic acid as intermediates. · The oxysterol 24S-hydroxycholesterol (formed in brain) was taken up by hepatocytes and partly metabolised into cholic acid, chenodeoxycholic acid and 5- cholestene-3beta,24S,27-triol. · 27-Hydroxycholesterol, the first product in the acidic pathway was found to be converted into bile acids less efficiently than 7alphahydroxycholesterol. Cheriodeoxycholic acid was found to be the major product. The findings suggest that the acidic pathway is responsible for a minor part of bile acid synthesis in human hepatocytes. · Glycine-conjugated and free bile acids suppressed bile acid synthesis and mRNA levels of cholesterol 7alpha-hydroxylase (CYP7A1) in the order CDCA > DCA > CA > UDCA. mRNA levels of sterol 12alpha-hydroxylase (CYP81B1) and especially sterol 27-hydroxylase (CYP27A1) were suppressed to a much lower degree than CYP7A1. · T3 dose-dependently decreased total bile acid formation in parallel with decreased expression of both CYP7A 1 and CYP8B 1. CA formation was inhibited to a higher degree than CDCA, resulting in a marked decrease in the CA / CDCA ratio. The results are in agreement with a number of previous in vivo studies in humans and emphasize that human hepatocytes cultured as above are suitable for studies on human bile acid formation.
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| 2. |
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| 3. |
- Zimmer, Christine L., et al.
(författare)
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A biliary immune landscape map of primary sclerosing cholangitis reveals a dominant network of neutrophils and tissue-resident T cells
- 2021
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Ingår i: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 13:599
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Tidskriftsartikel (refereegranskat)abstract
- The human biliary system, a mucosal barrier tissue connecting the liver and intestine, is an organ often affected by serious inflammatory and malignant diseases. Although these diseases are linked to immunological processes, the biliary system represents an unexplored immunological niche. By combining endoscopy-guided sampling of the biliary tree with a high-dimensional analysis approach, comprehensive mapping of the human biliary immunological landscape in patients with primary sclerosing cholangitis (PSC), a severe biliary inflammatory disease, was conducted. Major differences in immune cell composition in bile ducts compared to blood were revealed. Furthermore, biliary inflammation in patients with PSC was characterized by high presence of neutrophils and T cells as compared to control individuals without PSC. The biliary T cells displayed a CD103(+)CD69(+) effector memory phenotype, a combined gut and liver homing profile, and produced interleukin-17 (IL-17) and IL-22. Biliary neutrophil infiltration in PSC associated with CXCL8, possibly produced by resident T cells, and CXCL16 was linked to the enrichment of T cells. This study uncovers the immunological niche of human bile ducts, defines a local immune network between neutrophils and biliary-resident T cells in PSC, and provides a resource for future studies of the immune responses in biliary disorders.
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