{"id":6807,"date":"2017-04-21T11:15:19","date_gmt":"2017-04-21T15:15:19","guid":{"rendered":"https:\/\/web.uri.edu\/inbre\/?p=6807"},"modified":"2019-05-22T13:04:51","modified_gmt":"2019-05-22T17:04:51","slug":"peroxisome-proliferator-activated-receptor-alpha-as-integrator-of-bile-acid-and-inflammation-signaling","status":"publish","type":"post","link":"https:\/\/web.uri.edu\/riinbre\/peroxisome-proliferator-activated-receptor-alpha-as-integrator-of-bile-acid-and-inflammation-signaling\/","title":{"rendered":"Peroxisome proliferator-activated receptor alpha as integrator of bile acid and  Inflammation Signaling"},"content":{"rendered":"<p><strong>Investigator:<\/strong> Nisanne Ghonem, University of Rhode Island<\/p>\n<p><strong>Mentor:<\/strong> James Boyer, Yale University School of Medicine<\/p>\n<p><strong>Abstract:<\/strong><\/p>\n<p>Chronic cholestatic liver diseases result from an impairment of bile production and cause intracellular retention of bile acids (BAs) and subsequent cell toxicity and organ damage. Accumulation of toxic BAs is a significant contributor to disease progression.&nbsp; Cholestasis, or impaired bile flow, is characterized by inflammation and the destruction of hepatic bile ducts, for which no curative therapy exists. Complications of unresolved disease include prolonged inflammation, contributing to fibrosis, cirrhosis, and a high risk for malignancies. Very few therapies are available for cholestasis, i.e. ursodeoxycholic acid (UDCA), however, approximately 40% of patients have a sub- therapeutic response, while more advanced cases often do not. Strategies to reduce BA toxicity and inflammation will likely serve as complementary mechanisms to reduce disease progression. Peroxisome proliferator-activated receptor-alpha (PPAR\u03b1) is a nuclear hormone receptor highly expressed in the liver and it has a critical role in BA, cholesterol, and lipid regulation. PPAR\u03b1 maintains homeostasis by regulating transcription of genes responsible for BA synthesis, metabolism, and detoxification. PPAR\u03b1 also inhibits inflammation by blocking NF-\u03baB signaling pathways. Fenofibrate (FF) is FDA-approved to reduce elevated cholesterol and it is a PPAR\u03b1 agonist. Non-cholestatic volunteers showed that FF improved serum BA composition, rendering bile less toxic.&nbsp; Furthermore, clinical data showed that adjunct FF therapy improved liver biochemistries for patients with cholestasis not responding to UDCA. We hypothesize that activation of PPAR\u03b1 by fenofibrate promotes BA detoxification and inhibits NF-\u03baB -mediated transactivation of inflammation, thereby reduces BA toxicity and cholestatic liver injury.<\/p>\n<p><strong>Specific aim 1 <\/strong>will determine the role of FF on PPAR-mediated BA regulation and detoxification.&nbsp; Serum&nbsp; concentrations&nbsp; of&nbsp; free,&nbsp; conjugated&nbsp; primary and&nbsp; secondary&nbsp; BAs&nbsp; and&nbsp; their&nbsp; glucuronide metabolites&nbsp; from&nbsp; patients&nbsp; with&nbsp; cholestasis&nbsp; who&nbsp; have&nbsp; received&nbsp; FF&nbsp; therapy&nbsp; will&nbsp; be&nbsp; analyzed&nbsp; by&nbsp; LC-MS\/MS. Measurements pre- and post-FF therapy will serve as baseline comparisons for matched-pairs analysis. Signaling pathways of PPAR\u03b1 on BA metabolism and glucuronidation will be examined in vitro.<\/p>\n<p><strong>Specific aim 2 <\/strong>will characterize the inhibitory role of FF on NF-\u03baB-mediated inflammation. Serum pro-inflammatory cytokines will be measured from cholestatic patient samples pre- and post-FF therapy by ELISA. Additional mechanistic studies will examine the regulatory pathways of PPAR\u03b1 in mediating the anti-cholestatic effects in vitro. Together, these studies should identify the molecular basis for FF, an agent gaining increasing clinical interest for cholestasis, in reducing BA-induced liver injury and define the signaling pathway(s) of FF that regulate inflammation. If successful, these results would identify novel mechanisms of PPAR\u03b1 as a therapeutic target for cholestatic liver diseases.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Investigator: Nisanne Ghonem, University of Rhode Island Mentor: James Boyer, Yale University School of Medicine Abstract: Chronic cholestatic liver diseases result from an impairment of bile production and cause intracellular retention of bile acids (BAs) and subsequent cell toxicity and organ damage. Accumulation of toxic BAs is a significant contributor to disease progression.&nbsp; Cholestasis, or [&hellip;]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":"","_links_to":"","_links_to_target":""},"categories":[96],"tags":[],"class_list":["post-6807","post","type-post","status-publish","format-standard","hentry","category-research"],"acf":[],"_links":{"self":[{"href":"https:\/\/web.uri.edu\/riinbre\/wp-json\/wp\/v2\/posts\/6807","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/web.uri.edu\/riinbre\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/web.uri.edu\/riinbre\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/web.uri.edu\/riinbre\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/web.uri.edu\/riinbre\/wp-json\/wp\/v2\/comments?post=6807"}],"version-history":[{"count":1,"href":"https:\/\/web.uri.edu\/riinbre\/wp-json\/wp\/v2\/posts\/6807\/revisions"}],"predecessor-version":[{"id":12011,"href":"https:\/\/web.uri.edu\/riinbre\/wp-json\/wp\/v2\/posts\/6807\/revisions\/12011"}],"wp:attachment":[{"href":"https:\/\/web.uri.edu\/riinbre\/wp-json\/wp\/v2\/media?parent=6807"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/web.uri.edu\/riinbre\/wp-json\/wp\/v2\/categories?post=6807"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/web.uri.edu\/riinbre\/wp-json\/wp\/v2\/tags?post=6807"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}