The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer
Farnesoid X receptor (FXR) is a ligand-activated transcription factor involved in the control of bile acid (BA) synthesis and enterohepatic circulation. FXR can influence glucose and lipid homeostasis. Hepatic FXR activation by obeticholic acid is currently used to treat primary biliary cholangitis....
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| Veröffentlicht in: | Nature reviews. Gastroenterology & hepatology 2021-05, Vol.18 (5), p.335-347 |
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| description | Farnesoid X receptor (FXR) is a ligand-activated transcription factor involved in the control of bile acid (BA) synthesis and enterohepatic circulation. FXR can influence glucose and lipid homeostasis. Hepatic FXR activation by obeticholic acid is currently used to treat primary biliary cholangitis. Late-stage clinical trials investigating the use of obeticholic acid in the treatment of nonalcoholic steatohepatitis are underway. Mouse models of metabolic disease have demonstrated that inhibition of intestinal FXR signalling reduces obesity, insulin resistance and fatty liver disease by modulation of hepatic and gut bacteria-mediated BA metabolism, and intestinal ceramide synthesis. FXR also has a role in the pathogenesis of gastrointestinal and liver cancers. Studies using tissue-specific and global
Fxr
-null mice have revealed that FXR acts as a suppressor of hepatocellular carcinoma, mainly through regulating BA homeostasis. Loss of whole-body FXR potentiates progression of spontaneous colorectal cancer, and obesity-induced BA imbalance promotes intestinal stem cell proliferation by suppressing intestinal FXR in
Apc
min/+
mice. Owing to altered gut microbiota and FXR signalling, changes in overall BA levels and specific BA metabolites probably contribute to enterohepatic tumorigenesis. Modulating intestinal FXR signalling and altering BA metabolites are potential strategies for gastrointestinal and liver cancer prevention and treatment. In this Review, studies on the role of FXR in metabolic diseases and gastrointestinal and liver cancer are discussed, and the potential for development of targeted drugs are summarized.
Farnesoid X receptor (FXR) is involved in the control of bile acid synthesis and enterohepatic circulation. This Review discusses the role of FXR in metabolic diseases and gastrointestinal and liver cancers, highlighting underlying mechanisms and potential therapeutic targets.
Key points
Farnesoid X receptor (FXR) signalling in liver and intestine modulates enterohepatic bile acid circulation and lipid and glucose metabolism.
Both activation of hepatic FXR and inhibition of intestinal FXR have beneficial effects on obesity-related metabolic diseases.
As a transcriptional factor, FXR directly regulates expression of tumour suppressors involved in gastrointestinal and liver cancers.
The protective role of FXR in hepatocellular carcinoma mainly depends on hepatic modulation of bile acid homeostasis.
Tissue-specific FXR agonists and antagonist |
| doi_str_mv | 10.1038/s41575-020-00404-2 |
| format | Article |
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Fxr
-null mice have revealed that FXR acts as a suppressor of hepatocellular carcinoma, mainly through regulating BA homeostasis. Loss of whole-body FXR potentiates progression of spontaneous colorectal cancer, and obesity-induced BA imbalance promotes intestinal stem cell proliferation by suppressing intestinal FXR in
Apc
min/+
mice. Owing to altered gut microbiota and FXR signalling, changes in overall BA levels and specific BA metabolites probably contribute to enterohepatic tumorigenesis. Modulating intestinal FXR signalling and altering BA metabolites are potential strategies for gastrointestinal and liver cancer prevention and treatment. In this Review, studies on the role of FXR in metabolic diseases and gastrointestinal and liver cancer are discussed, and the potential for development of targeted drugs are summarized.
Farnesoid X receptor (FXR) is involved in the control of bile acid synthesis and enterohepatic circulation. This Review discusses the role of FXR in metabolic diseases and gastrointestinal and liver cancers, highlighting underlying mechanisms and potential therapeutic targets.
Key points
Farnesoid X receptor (FXR) signalling in liver and intestine modulates enterohepatic bile acid circulation and lipid and glucose metabolism.
Both activation of hepatic FXR and inhibition of intestinal FXR have beneficial effects on obesity-related metabolic diseases.
As a transcriptional factor, FXR directly regulates expression of tumour suppressors involved in gastrointestinal and liver cancers.
The protective role of FXR in hepatocellular carcinoma mainly depends on hepatic modulation of bile acid homeostasis.
Tissue-specific FXR agonists and antagonists should be explored as potentially clinical drugs for metabolic disease and cancer.
Gut microbiota-derived bile acid metabolism should be considered as a new drug target for development of therapeutic strategies.</description><identifier>ISSN: 1759-5045</identifier><identifier>EISSN: 1759-5053</identifier><identifier>DOI: 10.1038/s41575-020-00404-2</identifier><identifier>PMID: 33568795</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>692/4020/1503/1504/1885/1393 ; 692/4020/4021/1607/1610/4029 ; Acids ; Animal models ; Animals ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Bile ; Bile Acids and Salts - metabolism ; Biomarkers - metabolism ; Biomedicine ; Care and treatment ; Cell proliferation ; Cellular signal transduction ; Ceramide ; Chenodeoxycholic Acid - analogs & derivatives ; Chenodeoxycholic Acid - pharmacology ; Chenodeoxycholic Acid - therapeutic use ; Cholangitis ; Clinical trials ; Colorectal carcinoma ; Development and progression ; Digestive system ; Disease resistance ; Drug development ; Drug targeting ; Fatty liver ; Gastroenterology ; Gastrointestinal Agents - pharmacology ; Gastrointestinal Agents - therapeutic use ; Gastrointestinal cancer ; Gastrointestinal Microbiome - drug effects ; Gastrointestinal Microbiome - physiology ; Gastrointestinal Neoplasms - drug therapy ; Gastrointestinal Neoplasms - metabolism ; Gastrointestinal Neoplasms - microbiology ; Gastrointestinal tract ; Genetic aspects ; Health aspects ; Hepatocellular carcinoma ; Hepatology ; Homeostasis ; Humans ; Insulin ; Insulin resistance ; Intestinal microflora ; Intestine ; Liver cancer ; Liver diseases ; Liver Neoplasms - drug therapy ; Liver Neoplasms - metabolism ; Liver Neoplasms - microbiology ; Liver X receptors ; Medicine ; Medicine & Public Health ; Metabolic diseases ; Metabolic Diseases - drug therapy ; Metabolic Diseases - metabolism ; Metabolic Diseases - microbiology ; Metabolic disorders ; Metabolites ; Methods ; Mice ; Microbiota ; Obesity ; Receptors, Cytoplasmic and Nuclear - agonists ; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors ; Receptors, Cytoplasmic and Nuclear - metabolism ; Review Article ; Signal Transduction - drug effects ; Stem cells ; Therapeutic targets ; Transcription factors ; Tumorigenesis</subject><ispartof>Nature reviews. Gastroenterology & hepatology, 2021-05, Vol.18 (5), p.335-347</ispartof><rights>Springer Nature Limited 2021</rights><rights>COPYRIGHT 2021 Nature Publishing Group</rights><rights>Springer Nature Limited 2021.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c539t-36487dd0f5eb9bab099a54ace296ddef1f0e9c20042c42b389bd61aaf172e6bf3</citedby><cites>FETCH-LOGICAL-c539t-36487dd0f5eb9bab099a54ace296ddef1f0e9c20042c42b389bd61aaf172e6bf3</cites><orcidid>0000-0002-7990-2140 ; 0000-0001-8876-5099</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33568795$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sun, Lulu</creatorcontrib><creatorcontrib>Cai, Jie</creatorcontrib><creatorcontrib>Gonzalez, Frank J.</creatorcontrib><title>The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer</title><title>Nature reviews. Gastroenterology & hepatology</title><addtitle>Nat Rev Gastroenterol Hepatol</addtitle><addtitle>Nat Rev Gastroenterol Hepatol</addtitle><description>Farnesoid X receptor (FXR) is a ligand-activated transcription factor involved in the control of bile acid (BA) synthesis and enterohepatic circulation. FXR can influence glucose and lipid homeostasis. Hepatic FXR activation by obeticholic acid is currently used to treat primary biliary cholangitis. Late-stage clinical trials investigating the use of obeticholic acid in the treatment of nonalcoholic steatohepatitis are underway. Mouse models of metabolic disease have demonstrated that inhibition of intestinal FXR signalling reduces obesity, insulin resistance and fatty liver disease by modulation of hepatic and gut bacteria-mediated BA metabolism, and intestinal ceramide synthesis. FXR also has a role in the pathogenesis of gastrointestinal and liver cancers. Studies using tissue-specific and global
Fxr
-null mice have revealed that FXR acts as a suppressor of hepatocellular carcinoma, mainly through regulating BA homeostasis. Loss of whole-body FXR potentiates progression of spontaneous colorectal cancer, and obesity-induced BA imbalance promotes intestinal stem cell proliferation by suppressing intestinal FXR in
Apc
min/+
mice. Owing to altered gut microbiota and FXR signalling, changes in overall BA levels and specific BA metabolites probably contribute to enterohepatic tumorigenesis. Modulating intestinal FXR signalling and altering BA metabolites are potential strategies for gastrointestinal and liver cancer prevention and treatment. In this Review, studies on the role of FXR in metabolic diseases and gastrointestinal and liver cancer are discussed, and the potential for development of targeted drugs are summarized.
Farnesoid X receptor (FXR) is involved in the control of bile acid synthesis and enterohepatic circulation. This Review discusses the role of FXR in metabolic diseases and gastrointestinal and liver cancers, highlighting underlying mechanisms and potential therapeutic targets.
Key points
Farnesoid X receptor (FXR) signalling in liver and intestine modulates enterohepatic bile acid circulation and lipid and glucose metabolism.
Both activation of hepatic FXR and inhibition of intestinal FXR have beneficial effects on obesity-related metabolic diseases.
As a transcriptional factor, FXR directly regulates expression of tumour suppressors involved in gastrointestinal and liver cancers.
The protective role of FXR in hepatocellular carcinoma mainly depends on hepatic modulation of bile acid homeostasis.
Tissue-specific FXR agonists and antagonists should be explored as potentially clinical drugs for metabolic disease and cancer.
Gut microbiota-derived bile acid metabolism should be considered as a new drug target for development of therapeutic strategies.</description><subject>692/4020/1503/1504/1885/1393</subject><subject>692/4020/4021/1607/1610/4029</subject><subject>Acids</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Bile</subject><subject>Bile Acids and Salts - metabolism</subject><subject>Biomarkers - metabolism</subject><subject>Biomedicine</subject><subject>Care and treatment</subject><subject>Cell proliferation</subject><subject>Cellular signal transduction</subject><subject>Ceramide</subject><subject>Chenodeoxycholic Acid - analogs & derivatives</subject><subject>Chenodeoxycholic Acid - pharmacology</subject><subject>Chenodeoxycholic Acid - therapeutic use</subject><subject>Cholangitis</subject><subject>Clinical trials</subject><subject>Colorectal carcinoma</subject><subject>Development and progression</subject><subject>Digestive system</subject><subject>Disease resistance</subject><subject>Drug development</subject><subject>Drug targeting</subject><subject>Fatty liver</subject><subject>Gastroenterology</subject><subject>Gastrointestinal Agents - pharmacology</subject><subject>Gastrointestinal Agents - therapeutic use</subject><subject>Gastrointestinal cancer</subject><subject>Gastrointestinal Microbiome - drug effects</subject><subject>Gastrointestinal Microbiome - physiology</subject><subject>Gastrointestinal Neoplasms - drug therapy</subject><subject>Gastrointestinal Neoplasms - metabolism</subject><subject>Gastrointestinal Neoplasms - microbiology</subject><subject>Gastrointestinal tract</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Hepatocellular carcinoma</subject><subject>Hepatology</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Insulin</subject><subject>Insulin resistance</subject><subject>Intestinal microflora</subject><subject>Intestine</subject><subject>Liver cancer</subject><subject>Liver diseases</subject><subject>Liver Neoplasms - drug therapy</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - microbiology</subject><subject>Liver X receptors</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metabolic diseases</subject><subject>Metabolic Diseases - drug therapy</subject><subject>Metabolic Diseases - metabolism</subject><subject>Metabolic Diseases - microbiology</subject><subject>Metabolic disorders</subject><subject>Metabolites</subject><subject>Methods</subject><subject>Mice</subject><subject>Microbiota</subject><subject>Obesity</subject><subject>Receptors, Cytoplasmic and Nuclear - agonists</subject><subject>Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors</subject><subject>Receptors, Cytoplasmic and Nuclear - metabolism</subject><subject>Review Article</subject><subject>Signal Transduction - drug effects</subject><subject>Stem cells</subject><subject>Therapeutic targets</subject><subject>Transcription factors</subject><subject>Tumorigenesis</subject><issn>1759-5045</issn><issn>1759-5053</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kUtrVTEUhYMotlb_gAMJCOLAU_M8j2EpvqDgpIITCTnJzr0pOck1ySn4701769WKSAYJO99a2TsLoeeUnFLCx7dFUDnIjjDSESKI6NgDdEwHOXWSSP7wcBbyCD0p5YqQXko-PUZHnMt-HCZ5jL5dbgHnFAAnh53OEUryFn_FGQzsasrYR7xA1XMK3mDrC-gC5Q3W0eKNLjUnHyuU6qMOt8XgryFjo6OB_BQ9cjoUeHa3n6Av799dnn_sLj5_-HR-dtGZ1k_teC_GwVriJMzTrGcyTVoKbYBNvbXgqCMwGdaGZEawmY_TbHuqtaMDg352_AS93vvucvq-tm7U4ouBEHSEtBbFxDhKITgbG_ryL_Qqrbk13yjZnpBsaJ97oDY6gPLRpZq1uTFVZ31P2MDpKBp1-g-qLQuLNymC861-T_DqD8EWdKjbksJafYrlPsj2oMmplAxO7bJfdP6hKFE34at9-KqFr27DV6yJXtyNts4L2IPkV9oN4HugtKu4gfx79v_Y_gRLCLe4</recordid><startdate>20210501</startdate><enddate>20210501</enddate><creator>Sun, Lulu</creator><creator>Cai, Jie</creator><creator>Gonzalez, Frank J.</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-7990-2140</orcidid><orcidid>https://orcid.org/0000-0001-8876-5099</orcidid></search><sort><creationdate>20210501</creationdate><title>The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer</title><author>Sun, Lulu ; Cai, Jie ; Gonzalez, Frank J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c539t-36487dd0f5eb9bab099a54ace296ddef1f0e9c20042c42b389bd61aaf172e6bf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>692/4020/1503/1504/1885/1393</topic><topic>692/4020/4021/1607/1610/4029</topic><topic>Acids</topic><topic>Animal models</topic><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Bile</topic><topic>Bile Acids and Salts - metabolism</topic><topic>Biomarkers - metabolism</topic><topic>Biomedicine</topic><topic>Care and treatment</topic><topic>Cell proliferation</topic><topic>Cellular signal transduction</topic><topic>Ceramide</topic><topic>Chenodeoxycholic Acid - analogs & derivatives</topic><topic>Chenodeoxycholic Acid - pharmacology</topic><topic>Chenodeoxycholic Acid - therapeutic use</topic><topic>Cholangitis</topic><topic>Clinical trials</topic><topic>Colorectal carcinoma</topic><topic>Development and progression</topic><topic>Digestive system</topic><topic>Disease resistance</topic><topic>Drug development</topic><topic>Drug targeting</topic><topic>Fatty liver</topic><topic>Gastroenterology</topic><topic>Gastrointestinal Agents - pharmacology</topic><topic>Gastrointestinal Agents - therapeutic use</topic><topic>Gastrointestinal cancer</topic><topic>Gastrointestinal Microbiome - drug effects</topic><topic>Gastrointestinal Microbiome - physiology</topic><topic>Gastrointestinal Neoplasms - drug therapy</topic><topic>Gastrointestinal Neoplasms - metabolism</topic><topic>Gastrointestinal Neoplasms - microbiology</topic><topic>Gastrointestinal tract</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>Hepatocellular carcinoma</topic><topic>Hepatology</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Insulin</topic><topic>Insulin resistance</topic><topic>Intestinal microflora</topic><topic>Intestine</topic><topic>Liver cancer</topic><topic>Liver diseases</topic><topic>Liver Neoplasms - drug therapy</topic><topic>Liver Neoplasms - metabolism</topic><topic>Liver Neoplasms - microbiology</topic><topic>Liver X receptors</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metabolic diseases</topic><topic>Metabolic Diseases - drug therapy</topic><topic>Metabolic Diseases - metabolism</topic><topic>Metabolic Diseases - microbiology</topic><topic>Metabolic disorders</topic><topic>Metabolites</topic><topic>Methods</topic><topic>Mice</topic><topic>Microbiota</topic><topic>Obesity</topic><topic>Receptors, Cytoplasmic and Nuclear - agonists</topic><topic>Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors</topic><topic>Receptors, Cytoplasmic and Nuclear - metabolism</topic><topic>Review Article</topic><topic>Signal Transduction - drug effects</topic><topic>Stem cells</topic><topic>Therapeutic targets</topic><topic>Transcription factors</topic><topic>Tumorigenesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sun, Lulu</creatorcontrib><creatorcontrib>Cai, Jie</creatorcontrib><creatorcontrib>Gonzalez, Frank J.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Health and Medical</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest Biological Science Journals</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Nature reviews. Gastroenterology & hepatology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sun, Lulu</au><au>Cai, Jie</au><au>Gonzalez, Frank J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer</atitle><jtitle>Nature reviews. Gastroenterology & hepatology</jtitle><stitle>Nat Rev Gastroenterol Hepatol</stitle><addtitle>Nat Rev Gastroenterol Hepatol</addtitle><date>2021-05-01</date><risdate>2021</risdate><volume>18</volume><issue>5</issue><spage>335</spage><epage>347</epage><pages>335-347</pages><issn>1759-5045</issn><eissn>1759-5053</eissn><abstract>Farnesoid X receptor (FXR) is a ligand-activated transcription factor involved in the control of bile acid (BA) synthesis and enterohepatic circulation. FXR can influence glucose and lipid homeostasis. Hepatic FXR activation by obeticholic acid is currently used to treat primary biliary cholangitis. Late-stage clinical trials investigating the use of obeticholic acid in the treatment of nonalcoholic steatohepatitis are underway. Mouse models of metabolic disease have demonstrated that inhibition of intestinal FXR signalling reduces obesity, insulin resistance and fatty liver disease by modulation of hepatic and gut bacteria-mediated BA metabolism, and intestinal ceramide synthesis. FXR also has a role in the pathogenesis of gastrointestinal and liver cancers. Studies using tissue-specific and global
Fxr
-null mice have revealed that FXR acts as a suppressor of hepatocellular carcinoma, mainly through regulating BA homeostasis. Loss of whole-body FXR potentiates progression of spontaneous colorectal cancer, and obesity-induced BA imbalance promotes intestinal stem cell proliferation by suppressing intestinal FXR in
Apc
min/+
mice. Owing to altered gut microbiota and FXR signalling, changes in overall BA levels and specific BA metabolites probably contribute to enterohepatic tumorigenesis. Modulating intestinal FXR signalling and altering BA metabolites are potential strategies for gastrointestinal and liver cancer prevention and treatment. In this Review, studies on the role of FXR in metabolic diseases and gastrointestinal and liver cancer are discussed, and the potential for development of targeted drugs are summarized.
Farnesoid X receptor (FXR) is involved in the control of bile acid synthesis and enterohepatic circulation. This Review discusses the role of FXR in metabolic diseases and gastrointestinal and liver cancers, highlighting underlying mechanisms and potential therapeutic targets.
Key points
Farnesoid X receptor (FXR) signalling in liver and intestine modulates enterohepatic bile acid circulation and lipid and glucose metabolism.
Both activation of hepatic FXR and inhibition of intestinal FXR have beneficial effects on obesity-related metabolic diseases.
As a transcriptional factor, FXR directly regulates expression of tumour suppressors involved in gastrointestinal and liver cancers.
The protective role of FXR in hepatocellular carcinoma mainly depends on hepatic modulation of bile acid homeostasis.
Tissue-specific FXR agonists and antagonists should be explored as potentially clinical drugs for metabolic disease and cancer.
Gut microbiota-derived bile acid metabolism should be considered as a new drug target for development of therapeutic strategies.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>33568795</pmid><doi>10.1038/s41575-020-00404-2</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-7990-2140</orcidid><orcidid>https://orcid.org/0000-0001-8876-5099</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1759-5045 |
| ispartof | Nature reviews. Gastroenterology & hepatology, 2021-05, Vol.18 (5), p.335-347 |
| issn | 1759-5045 1759-5053 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2488544328 |
| source | MEDLINE; Alma/SFX Local Collection |
| subjects | 692/4020/1503/1504/1885/1393 692/4020/4021/1607/1610/4029 Acids Animal models Animals Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Bile Bile Acids and Salts - metabolism Biomarkers - metabolism Biomedicine Care and treatment Cell proliferation Cellular signal transduction Ceramide Chenodeoxycholic Acid - analogs & derivatives Chenodeoxycholic Acid - pharmacology Chenodeoxycholic Acid - therapeutic use Cholangitis Clinical trials Colorectal carcinoma Development and progression Digestive system Disease resistance Drug development Drug targeting Fatty liver Gastroenterology Gastrointestinal Agents - pharmacology Gastrointestinal Agents - therapeutic use Gastrointestinal cancer Gastrointestinal Microbiome - drug effects Gastrointestinal Microbiome - physiology Gastrointestinal Neoplasms - drug therapy Gastrointestinal Neoplasms - metabolism Gastrointestinal Neoplasms - microbiology Gastrointestinal tract Genetic aspects Health aspects Hepatocellular carcinoma Hepatology Homeostasis Humans Insulin Insulin resistance Intestinal microflora Intestine Liver cancer Liver diseases Liver Neoplasms - drug therapy Liver Neoplasms - metabolism Liver Neoplasms - microbiology Liver X receptors Medicine Medicine & Public Health Metabolic diseases Metabolic Diseases - drug therapy Metabolic Diseases - metabolism Metabolic Diseases - microbiology Metabolic disorders Metabolites Methods Mice Microbiota Obesity Receptors, Cytoplasmic and Nuclear - agonists Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors Receptors, Cytoplasmic and Nuclear - metabolism Review Article Signal Transduction - drug effects Stem cells Therapeutic targets Transcription factors Tumorigenesis |
| title | The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T11%3A59%3A15IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20role%20of%20farnesoid%20X%20receptor%20in%20metabolic%20diseases,%20and%20gastrointestinal%20and%20liver%20cancer&rft.jtitle=Nature%20reviews.%20Gastroenterology%20&%20hepatology&rft.au=Sun,%20Lulu&rft.date=2021-05-01&rft.volume=18&rft.issue=5&rft.spage=335&rft.epage=347&rft.pages=335-347&rft.issn=1759-5045&rft.eissn=1759-5053&rft_id=info:doi/10.1038/s41575-020-00404-2&rft_dat=%3Cgale_proqu%3EA660273184%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2520052710&rft_id=info:pmid/33568795&rft_galeid=A660273184&rfr_iscdi=true |