Frontiers in Clinical Drug Research-Diabetes and Obesity

Volume: 4

Interplay Between Bile Acid and GLP-1 Receptor Agonist Signaling Informs the Design of Drugs to Combat Obesity and its Metabolic Complications

Author(s): Jessica Felton and Jean-Pierre Raufman

Pp: 20-57 (38)

DOI: 10.2174/9781681084459119040004

* (Excluding Mailing and Handling)

Abstract

For more than a century the physiological role of bile acids was considered limited to their actions in cholesterol metabolism and lipid absorption from the gastrointestinal tract. Evidence emerging over the past 20 years has greatly changed this perspective. It is now apparent that these complex molecules play an integral signaling function within the gut and have extra-intestinal hormonal actions. Bile acid interaction with plasma membrane G protein-coupled receptors (e.g. TGR5, M3R) and nuclear receptors (e.g. FXR) expressed on intestinal epithelial cells modulates postreceptor signaling and gene transcription. Herein, we review the fundamentals of how bile acid structure governs the interaction of these molecules with cell receptors and transport proteins (e.g. ASBT), and how these interactions are important for nutritional balance. We focus on bile acid interaction with TGR5, a receptor whose activation stimulates release of glucagon-like peptide-1 (GLP-1) from enteroendocrine L cells; GLP-1, an intestinal incretin, is important for glucose homeostasis. Drugs that mimic the actions of GLP-1 or retard its degradation are effective treatments for diabetes, obesity, and their metabolic complications (e.g. non-alcoholic fatty liver disease). Altered gut and plasma levels of bile acids and GLP-1 are important for the clinical benefits of bariatric surgery. Hence, there is great interest in developing novel pharmaceutical approaches to imitate these changes and, in particular, the beneficial actions of bile acids. We offer a critical analysis of these approaches and propose novel opportunities for drug design to combat the current obesity epidemic and its metabolic complications.


Keywords: Bariatric surgery, Bile acids, Bile acid sequestrants, DPP4, Enteroendocrine L cells, Exenatide, FXR, Gastric bypass, GLP-1, Incretin, Metabolic syndrome, Non-Alcoholic fatty liver disease, Non-Alcoholic steatohepatitis, Obesity, Roux-en-Y, Sitagliptin, TGR5, Type 2 diabetes.

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      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
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      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1518
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 51461718 and j.to_ip >=51461718 )) and ((j.from_date <= 1740346481 and j.to_date >= 1740346481 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 12847) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 51461718 and j.to_ip >=51461718 )) and ((j.from_date <= 1740346481 and j.to_date >= 1740346481 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 12847) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 51461718 and j.to_ip >=51461718 )) and ((j.from_date <= 1740346481 and j.to_date >= 1740346481 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 12847)
      520μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1549
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` where `b`.`banner_ebook` = 1 and `bd`.`content_type` = 'B' and `bd`.`content_id` = 2247 and `b`.`banner_from_date` <= 1740346481 and `b`.`banner_to_date` >= 1740346481 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.07msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 2247
      • 3: 1740346481
      • 4: 1740346481
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='0fc535979d1a67cfcc3b68b38bfb59bc'
      280μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\Keywords
    18Keywords.php#?
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        HbxYepVhzQ9Jy3S2vB8dZUa7D2FtD4MwHzRIXAtn
        uc_cart_id
        0fc535979d1a67cfcc3b68b38bfb59bc
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/chapter/12847" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/12847
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:8 [ "accept-encoding" => array:1 [ 0 => "gzip, deflate" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] "connection" => array:1 [ 0 => "keep-alive" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] ]
        request_cookies
        []
        
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Sun, 23 Feb 2025 21:34:41 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IndCQ0ZNRXZzL0x5dHFrUGtUZzV2ZVE9PSIsInZhbHVlIjoiL3ZzMFdnVStBMGpuMVlZUzVRUm1FdWlLK0k4K0UyV3E0SndyeWZId01nKzl2aVR3bWE1SlhzcERYcWNWc2IvSktJZzdXc3EyT24yTFpNWjNITDBHT3lweHdxOTQ5YnVWakVVaWwzcC9sTXBnTGhaK3Z2ZUx2eHgwU21xSXlkVmoiLCJtYWMiOiI3OWUyMzhkMGNiODJkMWFhZmFkNzIwZTk4MjdjNWNlNmExNzM2OGFlNWE5MzQzZTg0NTA0ZTQ1YTdlZGUyYjdjIiwidGFnIjoiIn0%3D; expires=Wed, 26 Feb 2025 09:34:41 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IndCQ0ZNRXZzL0x5dHFrUGtUZzV2ZVE9PSIsInZhbHVlIjoiL3ZzMFdnVStBMGpuMVlZUzVRUm1FdWlLK0k4K0UyV3E0SndyeWZId01nKzl2aVR3bWE1SlhzcERYcWNWc2IvSktJZzdXc" 1 => "alphaeurekaselectnet_session=eyJpdiI6IitQNGNnUmNVNWNXNEdid04xcXFhR3c9PSIsInZhbHVlIjoiNUhxcENxMFczeHhraDlMcU1DdDMvVDU4YjVxNjQwdnBnR21DNnNROGE3dDQ4M0t5QVFVVkhOWU5ZbHRiaU9pUUxXY1RnWUdzcHdwUlJVL3JkS203NitCUzZVbW5zamxuQU5hUkp0bThqMTJ0TWFxKzVRZXRxTHV2NkFFME9DMlQiLCJtYWMiOiJhNTBiZDBlZTdkYTM5NDJhM2UxZDE2YTUxZDk2MTZlOTNmZjhhNzIxNTg5NDEyYzkzOTVmNTIwY2UzMGJmMGIwIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IitQNGNnUmNVNWNXNEdid04xcXFhR3c9PSIsInZhbHVlIjoiNUhxcENxMFczeHhraDlMcU1DdDMvVDU4YjVxNjQwdnBnR21DNnNROGE3dDQ4M0t5QVFVVkhOWU5" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IndCQ0ZNRXZzL0x5dHFrUGtUZzV2ZVE9PSIsInZhbHVlIjoiL3ZzMFdnVStBMGpuMVlZUzVRUm1FdWlLK0k4K0UyV3E0SndyeWZId01nKzl2aVR3bWE1SlhzcERYcWNWc2IvSktJZzdXc3EyT24yTFpNWjNITDBHT3lweHdxOTQ5YnVWakVVaWwzcC9sTXBnTGhaK3Z2ZUx2eHgwU21xSXlkVmoiLCJtYWMiOiI3OWUyMzhkMGNiODJkMWFhZmFkNzIwZTk4MjdjNWNlNmExNzM2OGFlNWE5MzQzZTg0NTA0ZTQ1YTdlZGUyYjdjIiwidGFnIjoiIn0%3D; expires=Wed, 26-Feb-2025 09:34:41 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IndCQ0ZNRXZzL0x5dHFrUGtUZzV2ZVE9PSIsInZhbHVlIjoiL3ZzMFdnVStBMGpuMVlZUzVRUm1FdWlLK0k4K0UyV3E0SndyeWZId01nKzl2aVR3bWE1SlhzcERYcWNWc2IvSktJZzdXc" 1 => "alphaeurekaselectnet_session=eyJpdiI6IitQNGNnUmNVNWNXNEdid04xcXFhR3c9PSIsInZhbHVlIjoiNUhxcENxMFczeHhraDlMcU1DdDMvVDU4YjVxNjQwdnBnR21DNnNROGE3dDQ4M0t5QVFVVkhOWU5ZbHRiaU9pUUxXY1RnWUdzcHdwUlJVL3JkS203NitCUzZVbW5zamxuQU5hUkp0bThqMTJ0TWFxKzVRZXRxTHV2NkFFME9DMlQiLCJtYWMiOiJhNTBiZDBlZTdkYTM5NDJhM2UxZDE2YTUxZDk2MTZlOTNmZjhhNzIxNTg5NDEyYzkzOTVmNTIwY2UzMGJmMGIwIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IitQNGNnUmNVNWNXNEdid04xcXFhR3c9PSIsInZhbHVlIjoiNUhxcENxMFczeHhraDlMcU1DdDMvVDU4YjVxNjQwdnBnR21DNnNROGE3dDQ4M0t5QVFVVkhOWU5" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "HbxYepVhzQ9Jy3S2vB8dZUa7D2FtD4MwHzRIXAtn" "uc_cart_id" => "0fc535979d1a67cfcc3b68b38bfb59bc" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/chapter/12847" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-23 21:34:41GET/chapter/128471121920