Bile Acid Sequestrant, Sevelamer Ameliorates Hepatic Fibrosis with Reduced Overload of Endogenous Lipopolysaccharide in Experimental Nonalcoholic Steatohepatitis
Despite the use of various pharmacotherapeutic strategies, fibrosis due to nonalcoholic steatohepatitis (NASH) remains an unsatisfied clinical issue. We investigated the effect of sevelamer, a hydrophilic bile acid sequestrant, on hepatic fibrosis in a murine NASH model. Male C57BL/6J mice were fed a choline-deficient, L-amino acid-defined, high-fat (CDHF) diet for 12 weeks with or without orally administered sevelamer hydrochloride (2% per diet weight). Histological and biochemical analyses revealed that sevelamer prevented hepatic steatosis, macrophage infiltration, and pericellular fibrosis in CDHF-fed mice. Sevelamer reduced the portal levels of total bile acid and inhibited both hepatic and intestinal farnesoid X receptor activation. Gut microbiome analysis demonstrated that sevelamer improved a lower α-diversity and prevented decreases in Lactobacillaceae and Clostridiaceae as well as increases in Desulfovibrionaceae and Enterobacteriaceae in the CDHF-fed mice. Additionally, sevelamer bound to lipopolysaccharide (LPS) in the intestinal lumen and promoted its fecal excretion. Consequently, the sevelamer treatment restored the tight intestinal junction proteins and reduced the portal LPS levels, leading to the suppression of hepatic toll-like receptor 4 signaling pathway. Furthermore, sevelamer inhibited the LPS-mediated induction of fibrogenic activity in human hepatic stellate cells in vitro. Collectively, sevelamer inhibited the development of murine steatohepatitis by reducing hepatic LPS overload.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
|---|---|
| Enthalten in: |
Microorganisms - 8(2020), 6 vom: 19. Juni |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Tsuji, Yuki [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Journal Article |
|---|
| Anmerkungen: |
Date Revised 28.09.2020 published: Electronic Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.3390/microorganisms8060925 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM311538495 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM311538495 | ||
| 003 | DE-627 | ||
| 005 | 20231225142452.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3390/microorganisms8060925 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1038.xml |
| 035 | |a (DE-627)NLM311538495 | ||
| 035 | |a (NLM)32575352 | ||
| 035 | |a (PII)E925 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Tsuji, Yuki |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Bile Acid Sequestrant, Sevelamer Ameliorates Hepatic Fibrosis with Reduced Overload of Endogenous Lipopolysaccharide in Experimental Nonalcoholic Steatohepatitis |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 28.09.2020 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a Despite the use of various pharmacotherapeutic strategies, fibrosis due to nonalcoholic steatohepatitis (NASH) remains an unsatisfied clinical issue. We investigated the effect of sevelamer, a hydrophilic bile acid sequestrant, on hepatic fibrosis in a murine NASH model. Male C57BL/6J mice were fed a choline-deficient, L-amino acid-defined, high-fat (CDHF) diet for 12 weeks with or without orally administered sevelamer hydrochloride (2% per diet weight). Histological and biochemical analyses revealed that sevelamer prevented hepatic steatosis, macrophage infiltration, and pericellular fibrosis in CDHF-fed mice. Sevelamer reduced the portal levels of total bile acid and inhibited both hepatic and intestinal farnesoid X receptor activation. Gut microbiome analysis demonstrated that sevelamer improved a lower α-diversity and prevented decreases in Lactobacillaceae and Clostridiaceae as well as increases in Desulfovibrionaceae and Enterobacteriaceae in the CDHF-fed mice. Additionally, sevelamer bound to lipopolysaccharide (LPS) in the intestinal lumen and promoted its fecal excretion. Consequently, the sevelamer treatment restored the tight intestinal junction proteins and reduced the portal LPS levels, leading to the suppression of hepatic toll-like receptor 4 signaling pathway. Furthermore, sevelamer inhibited the LPS-mediated induction of fibrogenic activity in human hepatic stellate cells in vitro. Collectively, sevelamer inhibited the development of murine steatohepatitis by reducing hepatic LPS overload | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a lipopolysaccharide | |
| 650 | 4 | |a nonalcoholic steatohepatitis | |
| 650 | 4 | |a sevelamer | |
| 650 | 4 | |a toll-like receptor 4 | |
| 700 | 1 | |a Kaji, Kosuke |e verfasserin |4 aut | |
| 700 | 1 | |a Kitade, Mitsuteru |e verfasserin |4 aut | |
| 700 | 1 | |a Kaya, Daisuke |e verfasserin |4 aut | |
| 700 | 1 | |a Kitagawa, Koh |e verfasserin |4 aut | |
| 700 | 1 | |a Ozutsumi, Takahiro |e verfasserin |4 aut | |
| 700 | 1 | |a Fujinaga, Yukihisa |e verfasserin |4 aut | |
| 700 | 1 | |a Takaya, Hiroaki |e verfasserin |4 aut | |
| 700 | 1 | |a Kawaratani, Hideto |e verfasserin |4 aut | |
| 700 | 1 | |a Namisaki, Tadashi |e verfasserin |4 aut | |
| 700 | 1 | |a Moriya, Kei |e verfasserin |4 aut | |
| 700 | 1 | |a Akahane, Takemi |e verfasserin |4 aut | |
| 700 | 1 | |a Yoshiji, Hitoshi |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Microorganisms |d 2013 |g 8(2020), 6 vom: 19. Juni |w (DE-627)NLM247050237 |x 2076-2607 |7 nnns |
| 773 | 1 | 8 | |g volume:8 |g year:2020 |g number:6 |g day:19 |g month:06 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.3390/microorganisms8060925 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 8 |j 2020 |e 6 |b 19 |c 06 | ||