Nonalcoholic Fatty Liver Disease and Hypercholesterolemia: Roles of Thyroid Hormones, Metabolites, and Agonists
Background: Thyroid hormones (THs) exert a strong influence on mammalian lipid metabolism at the systemic and hepatic levels by virtue of their roles in regulating circulating lipoprotein, triglyceride (TAG), and cholesterol levels, as well as hepatic TAG storage and metabolism. These effects are me...
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| Veröffentlicht in: | Thyroid (New York, N.Y.) N.Y.), 2019-09, Vol.29 (9), p.1173-1191 |
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| creator | Sinha, Rohit A. Bruinstroop, Eveline Singh, Brijesh K. Yen, Paul M. |
| description | Background:
Thyroid hormones (THs) exert a strong influence on mammalian lipid metabolism at the systemic and hepatic levels by virtue of their roles in regulating circulating lipoprotein, triglyceride (TAG), and cholesterol levels, as well as hepatic TAG storage and metabolism. These effects are mediated by intricate sensing and feedback systems that function at the physiological, metabolic, molecular, and transcriptional levels in the liver. Dysfunction in the pathways involved in lipid metabolism disrupts hepatic lipid homeostasis and contributes to the pathogenesis of metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD) and hypercholesterolemia. There has been strong interest in understanding and employing THs, TH metabolites, and TH mimetics as lipid-modifying drugs.
Summary:
THs regulate many processes involved in hepatic TAG and cholesterol metabolism to decrease serum cholesterol and intrahepatic lipid content. TH receptor β analogs designed to have less side effects than the natural hormone are currently being tested in phase II clinical studies for NAFLD and hypercholesterolemia. The TH metabolites, 3,5-diiodo-
l
-thyronine (T2) and T1AM (3-iodothyronamine), have different beneficial effects on lipid metabolism compared with triiodothyronine (T3), although their clinical application is still under investigation. Also, prodrugs and glucagon/T3 conjugates have been developed that direct TH to the liver.
Conclusions:
TH-based therapies show clinical promise for the treatment of NAFLD and hypercholesterolemia. Strategies for limiting side effects of TH are being developed and may enable TH metabolites and analogs to have specific effects in the liver for treatments of these conditions. These liver-specific effects and potential suppression of the hypothalamic/pituitary/thyroid axis raise the issue of monitoring liver-specific markers of TH action to assess clinical efficacy and dosing of these compounds. |
| doi_str_mv | 10.1089/thy.2018.0664 |
| format | Article |
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Thyroid hormones (THs) exert a strong influence on mammalian lipid metabolism at the systemic and hepatic levels by virtue of their roles in regulating circulating lipoprotein, triglyceride (TAG), and cholesterol levels, as well as hepatic TAG storage and metabolism. These effects are mediated by intricate sensing and feedback systems that function at the physiological, metabolic, molecular, and transcriptional levels in the liver. Dysfunction in the pathways involved in lipid metabolism disrupts hepatic lipid homeostasis and contributes to the pathogenesis of metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD) and hypercholesterolemia. There has been strong interest in understanding and employing THs, TH metabolites, and TH mimetics as lipid-modifying drugs.
Summary:
THs regulate many processes involved in hepatic TAG and cholesterol metabolism to decrease serum cholesterol and intrahepatic lipid content. TH receptor β analogs designed to have less side effects than the natural hormone are currently being tested in phase II clinical studies for NAFLD and hypercholesterolemia. The TH metabolites, 3,5-diiodo-
l
-thyronine (T2) and T1AM (3-iodothyronamine), have different beneficial effects on lipid metabolism compared with triiodothyronine (T3), although their clinical application is still under investigation. Also, prodrugs and glucagon/T3 conjugates have been developed that direct TH to the liver.
Conclusions:
TH-based therapies show clinical promise for the treatment of NAFLD and hypercholesterolemia. Strategies for limiting side effects of TH are being developed and may enable TH metabolites and analogs to have specific effects in the liver for treatments of these conditions. These liver-specific effects and potential suppression of the hypothalamic/pituitary/thyroid axis raise the issue of monitoring liver-specific markers of TH action to assess clinical efficacy and dosing of these compounds.</description><identifier>ISSN: 1050-7256</identifier><identifier>EISSN: 1557-9077</identifier><identifier>DOI: 10.1089/thy.2018.0664</identifier><identifier>PMID: 31389309</identifier><language>eng</language><publisher>United States: Mary Ann Liebert, Inc., publishers</publisher><subject>Animals ; Humans ; Hypercholesterolemia - drug therapy ; Hypercholesterolemia - metabolism ; Lipid Metabolism ; Liver - metabolism ; Mice ; Non-alcoholic Fatty Liver Disease - drug therapy ; Non-alcoholic Fatty Liver Disease - metabolism ; Receptors, Thyroid Hormone - physiology ; Review and Scholarly Dialog ; Thyroid Hormones - agonists ; Thyroid Hormones - physiology ; Thyroid Hormones - therapeutic use</subject><ispartof>Thyroid (New York, N.Y.), 2019-09, Vol.29 (9), p.1173-1191</ispartof><rights>2019, Mary Ann Liebert, Inc., publishers</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c541t-f433a8ac3c8ef73a09f6fb7586b929c41779b682fcfc6ba032572600af4f30203</citedby><cites>FETCH-LOGICAL-c541t-f433a8ac3c8ef73a09f6fb7586b929c41779b682fcfc6ba032572600af4f30203</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31389309$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sinha, Rohit A.</creatorcontrib><creatorcontrib>Bruinstroop, Eveline</creatorcontrib><creatorcontrib>Singh, Brijesh K.</creatorcontrib><creatorcontrib>Yen, Paul M.</creatorcontrib><title>Nonalcoholic Fatty Liver Disease and Hypercholesterolemia: Roles of Thyroid Hormones, Metabolites, and Agonists</title><title>Thyroid (New York, N.Y.)</title><addtitle>Thyroid</addtitle><description>Background:
Thyroid hormones (THs) exert a strong influence on mammalian lipid metabolism at the systemic and hepatic levels by virtue of their roles in regulating circulating lipoprotein, triglyceride (TAG), and cholesterol levels, as well as hepatic TAG storage and metabolism. These effects are mediated by intricate sensing and feedback systems that function at the physiological, metabolic, molecular, and transcriptional levels in the liver. Dysfunction in the pathways involved in lipid metabolism disrupts hepatic lipid homeostasis and contributes to the pathogenesis of metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD) and hypercholesterolemia. There has been strong interest in understanding and employing THs, TH metabolites, and TH mimetics as lipid-modifying drugs.
Summary:
THs regulate many processes involved in hepatic TAG and cholesterol metabolism to decrease serum cholesterol and intrahepatic lipid content. TH receptor β analogs designed to have less side effects than the natural hormone are currently being tested in phase II clinical studies for NAFLD and hypercholesterolemia. The TH metabolites, 3,5-diiodo-
l
-thyronine (T2) and T1AM (3-iodothyronamine), have different beneficial effects on lipid metabolism compared with triiodothyronine (T3), although their clinical application is still under investigation. Also, prodrugs and glucagon/T3 conjugates have been developed that direct TH to the liver.
Conclusions:
TH-based therapies show clinical promise for the treatment of NAFLD and hypercholesterolemia. Strategies for limiting side effects of TH are being developed and may enable TH metabolites and analogs to have specific effects in the liver for treatments of these conditions. These liver-specific effects and potential suppression of the hypothalamic/pituitary/thyroid axis raise the issue of monitoring liver-specific markers of TH action to assess clinical efficacy and dosing of these compounds.</description><subject>Animals</subject><subject>Humans</subject><subject>Hypercholesterolemia - drug therapy</subject><subject>Hypercholesterolemia - metabolism</subject><subject>Lipid Metabolism</subject><subject>Liver - metabolism</subject><subject>Mice</subject><subject>Non-alcoholic Fatty Liver Disease - drug therapy</subject><subject>Non-alcoholic Fatty Liver Disease - metabolism</subject><subject>Receptors, Thyroid Hormone - physiology</subject><subject>Review and Scholarly Dialog</subject><subject>Thyroid Hormones - agonists</subject><subject>Thyroid Hormones - physiology</subject><subject>Thyroid Hormones - therapeutic use</subject><issn>1050-7256</issn><issn>1557-9077</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcFvFCEUh4nR2Fo9ejUcPTjrAwYYPJg01VqTVRNTz4Sh0MXMwApsk_nvZbK10ZOnx4Mv33vkh9BLAhsCg3pbd8uGAhk2IET_CJ0SzmWnQMrH7QwcOkm5OEHPSvkJQMQg2VN0wggbFAN1itLXFM1k0y5NweJLU-uCt-HOZfwhFGeKwybe4Ktl77JtjCvV5VbmYN7h72uPk8fXuyWn0LCU5xRdeYO_uGrGpqxrsxrOb1MMpZbn6Ik3U3Ev7usZ-nH58friqtt--_T54nzbWd6T2vmeMTMYy-zgvGQGlBd-lHwQo6LK9kRKNYqBeuutGA0wyiUVAMb3ngEFdobeH737wzi7G-tizWbS-xxmkxedTND_vsSw07fpTouBgwLeBK_vBTn9OrR_6zkU66bJRJcORVMqFFOcsHVWd0RtTqVk5x_GENBrSLqFpNeQ9BpS41_9vdsD_SeVBrAjsF6bGKfgRpfrf7S_AbaEoTs</recordid><startdate>20190901</startdate><enddate>20190901</enddate><creator>Sinha, Rohit A.</creator><creator>Bruinstroop, Eveline</creator><creator>Singh, Brijesh K.</creator><creator>Yen, Paul M.</creator><general>Mary Ann Liebert, Inc., publishers</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20190901</creationdate><title>Nonalcoholic Fatty Liver Disease and Hypercholesterolemia: Roles of Thyroid Hormones, Metabolites, and Agonists</title><author>Sinha, Rohit A. ; Bruinstroop, Eveline ; Singh, Brijesh K. ; Yen, Paul M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c541t-f433a8ac3c8ef73a09f6fb7586b929c41779b682fcfc6ba032572600af4f30203</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Humans</topic><topic>Hypercholesterolemia - drug therapy</topic><topic>Hypercholesterolemia - metabolism</topic><topic>Lipid Metabolism</topic><topic>Liver - metabolism</topic><topic>Mice</topic><topic>Non-alcoholic Fatty Liver Disease - drug therapy</topic><topic>Non-alcoholic Fatty Liver Disease - metabolism</topic><topic>Receptors, Thyroid Hormone - physiology</topic><topic>Review and Scholarly Dialog</topic><topic>Thyroid Hormones - agonists</topic><topic>Thyroid Hormones - physiology</topic><topic>Thyroid Hormones - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sinha, Rohit A.</creatorcontrib><creatorcontrib>Bruinstroop, Eveline</creatorcontrib><creatorcontrib>Singh, Brijesh K.</creatorcontrib><creatorcontrib>Yen, Paul M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Thyroid (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sinha, Rohit A.</au><au>Bruinstroop, Eveline</au><au>Singh, Brijesh K.</au><au>Yen, Paul M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nonalcoholic Fatty Liver Disease and Hypercholesterolemia: Roles of Thyroid Hormones, Metabolites, and Agonists</atitle><jtitle>Thyroid (New York, N.Y.)</jtitle><addtitle>Thyroid</addtitle><date>2019-09-01</date><risdate>2019</risdate><volume>29</volume><issue>9</issue><spage>1173</spage><epage>1191</epage><pages>1173-1191</pages><issn>1050-7256</issn><eissn>1557-9077</eissn><abstract>Background:
Thyroid hormones (THs) exert a strong influence on mammalian lipid metabolism at the systemic and hepatic levels by virtue of their roles in regulating circulating lipoprotein, triglyceride (TAG), and cholesterol levels, as well as hepatic TAG storage and metabolism. These effects are mediated by intricate sensing and feedback systems that function at the physiological, metabolic, molecular, and transcriptional levels in the liver. Dysfunction in the pathways involved in lipid metabolism disrupts hepatic lipid homeostasis and contributes to the pathogenesis of metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD) and hypercholesterolemia. There has been strong interest in understanding and employing THs, TH metabolites, and TH mimetics as lipid-modifying drugs.
Summary:
THs regulate many processes involved in hepatic TAG and cholesterol metabolism to decrease serum cholesterol and intrahepatic lipid content. TH receptor β analogs designed to have less side effects than the natural hormone are currently being tested in phase II clinical studies for NAFLD and hypercholesterolemia. The TH metabolites, 3,5-diiodo-
l
-thyronine (T2) and T1AM (3-iodothyronamine), have different beneficial effects on lipid metabolism compared with triiodothyronine (T3), although their clinical application is still under investigation. Also, prodrugs and glucagon/T3 conjugates have been developed that direct TH to the liver.
Conclusions:
TH-based therapies show clinical promise for the treatment of NAFLD and hypercholesterolemia. Strategies for limiting side effects of TH are being developed and may enable TH metabolites and analogs to have specific effects in the liver for treatments of these conditions. These liver-specific effects and potential suppression of the hypothalamic/pituitary/thyroid axis raise the issue of monitoring liver-specific markers of TH action to assess clinical efficacy and dosing of these compounds.</abstract><cop>United States</cop><pub>Mary Ann Liebert, Inc., publishers</pub><pmid>31389309</pmid><doi>10.1089/thy.2018.0664</doi><tpages>19</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Alma/SFX Local Collection |
| subjects | Animals Humans Hypercholesterolemia - drug therapy Hypercholesterolemia - metabolism Lipid Metabolism Liver - metabolism Mice Non-alcoholic Fatty Liver Disease - drug therapy Non-alcoholic Fatty Liver Disease - metabolism Receptors, Thyroid Hormone - physiology Review and Scholarly Dialog Thyroid Hormones - agonists Thyroid Hormones - physiology Thyroid Hormones - therapeutic use |
| title | Nonalcoholic Fatty Liver Disease and Hypercholesterolemia: Roles of Thyroid Hormones, Metabolites, and Agonists |
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