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Hepatic NAD+ deficiency as a therapeutic target for non‐alcoholic fatty liver disease in ageing
Background and Purpose Ageing is an important risk factor of non‐alcoholic fatty liver disease (NAFLD). Here, we investigated whether the deficiency of nicotinamide adenine dinucleotide (NAD+), a ubiquitous coenzyme, links ageing with NAFLD. Experimental Approach Hepatic concentrations of NAD+, prot...
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| Published in: | British journal of pharmacology 2016-08, Vol.173 (15), p.2352-2368 |
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| container_title | British journal of pharmacology |
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| creator | Zhou, Can‐Can Yang, Xi Hua, Xia Liu, Jian Fan, Mao‐Bing Li, Guo‐Qiang Song, Jie Xu, Tian‐Ying Li, Zhi‐Yong Guan, Yun‐Feng Wang, Pei Miao, Chao‐Yu |
| description | Background and Purpose
Ageing is an important risk factor of non‐alcoholic fatty liver disease (NAFLD). Here, we investigated whether the deficiency of nicotinamide adenine dinucleotide (NAD+), a ubiquitous coenzyme, links ageing with NAFLD.
Experimental Approach
Hepatic concentrations of NAD+, protein levels of nicotinamide phosphoribosyltransferase (NAMPT) and several other critical enzymes regulating NAD+ biosynthesis, were compared in middle‐aged and aged mice or patients. The influences of NAD+ decline on the steatosis and steatohepatitis were evaluated in wild‐type and H247A dominant‐negative, enzymically‐inactive NAMPT transgenic mice (DN‐NAMPT) given normal or high‐fat diet (HFD).
Key Results
Hepatic NAD+ level decreased in aged mice and humans. NAMPT‐controlled NAD+ salvage, but not de novo biosynthesis pathway, was compromised in liver of elderly mice and humans. Given normal chow, middle‐age DN‐NAMPT mice displayed systemic NAD+ reduction and had moderate NAFLD phenotypes, including lipid accumulation, enhanced oxidative stress, triggered inflammation and impaired insulin sensitivity in liver. All these NAFLD phenotypes, especially release of pro‐inflammatory factors, Kupffer cell accumulation, monocytes infiltration, NLRP3 inflammasome pathway and hepatic fibrosis (Masson's staining and α‐SMA staining), deteriorated further under HFD challenge. Oral administration of nicotinamide riboside, a natural NAD+ precursor, completely corrected these NAFLD phenotypes induced by NAD+ deficiency alone or HFD, whereas adenovirus‐mediated SIRT1 overexpression only partially rescued these phenotypes.
Conclusions and Implications
These results provide the first evidence that ageing‐associated NAD+ deficiency is a critical risk factor for NAFLD, and suggest that supplementation with NAD+ substrates may be a promising therapeutic strategy to prevent and treat NAFLD. |
| doi_str_mv | 10.1111/bph.13513 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4945761</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1804864913</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3733-6efe98d48150f12a2a86066f146a9656adad9c01f524db97113446f3efb67c043</originalsourceid><addsrcrecordid>eNp1kc9u1DAQhy0EokvhwAsgS1xAKK0ndpzkglTKn0WqgAOcrVlnvOsqG6d2UrQ3HoFn5EnwsqUCJOYyh9-nTzP6MfYYxAnkOV2NmxOQFcg7bAGq1kUlG7jLFkKIugBomiP2IKVLIXJYV_fZUVlDraRWC4ZLGnHyln84e_2Cd-S89TTYHcfEkU8bijjSvAcmjGuauAuRD2H48e079jZsQp8jh9O0472_psg7nwgTcT9wXJMf1g_ZPYd9okc3-5h9efvm8_myuPj47v352UVhZS1loclR23SqgUo4KLHERgutHSiNra40dti1VoCrStWt2hpAKqWdJLfStRVKHrOXB-84r7bUWRqmiL0Zo99i3JmA3vydDH5j1uHaqFZVtYYseHYjiOFqpjSZrU-W-h4HCnMy0AjVaNWCzOjTf9DLMMchv7enZNs2ZSky9fxA2RhSiuRujwFh9sWZXJz5VVxmn_x5_S35u6kMnB6Ar76n3f9N5tWn5UH5Ey7kot4</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1803998220</pqid></control><display><type>article</type><title>Hepatic NAD+ deficiency as a therapeutic target for non‐alcoholic fatty liver disease in ageing</title><source>Wiley</source><source>Wiley Blackwell Single Titles</source><source>PubMed Central</source><creator>Zhou, Can‐Can ; Yang, Xi ; Hua, Xia ; Liu, Jian ; Fan, Mao‐Bing ; Li, Guo‐Qiang ; Song, Jie ; Xu, Tian‐Ying ; Li, Zhi‐Yong ; Guan, Yun‐Feng ; Wang, Pei ; Miao, Chao‐Yu</creator><creatorcontrib>Zhou, Can‐Can ; Yang, Xi ; Hua, Xia ; Liu, Jian ; Fan, Mao‐Bing ; Li, Guo‐Qiang ; Song, Jie ; Xu, Tian‐Ying ; Li, Zhi‐Yong ; Guan, Yun‐Feng ; Wang, Pei ; Miao, Chao‐Yu</creatorcontrib><description>Background and Purpose
Ageing is an important risk factor of non‐alcoholic fatty liver disease (NAFLD). Here, we investigated whether the deficiency of nicotinamide adenine dinucleotide (NAD+), a ubiquitous coenzyme, links ageing with NAFLD.
Experimental Approach
Hepatic concentrations of NAD+, protein levels of nicotinamide phosphoribosyltransferase (NAMPT) and several other critical enzymes regulating NAD+ biosynthesis, were compared in middle‐aged and aged mice or patients. The influences of NAD+ decline on the steatosis and steatohepatitis were evaluated in wild‐type and H247A dominant‐negative, enzymically‐inactive NAMPT transgenic mice (DN‐NAMPT) given normal or high‐fat diet (HFD).
Key Results
Hepatic NAD+ level decreased in aged mice and humans. NAMPT‐controlled NAD+ salvage, but not de novo biosynthesis pathway, was compromised in liver of elderly mice and humans. Given normal chow, middle‐age DN‐NAMPT mice displayed systemic NAD+ reduction and had moderate NAFLD phenotypes, including lipid accumulation, enhanced oxidative stress, triggered inflammation and impaired insulin sensitivity in liver. All these NAFLD phenotypes, especially release of pro‐inflammatory factors, Kupffer cell accumulation, monocytes infiltration, NLRP3 inflammasome pathway and hepatic fibrosis (Masson's staining and α‐SMA staining), deteriorated further under HFD challenge. Oral administration of nicotinamide riboside, a natural NAD+ precursor, completely corrected these NAFLD phenotypes induced by NAD+ deficiency alone or HFD, whereas adenovirus‐mediated SIRT1 overexpression only partially rescued these phenotypes.
Conclusions and Implications
These results provide the first evidence that ageing‐associated NAD+ deficiency is a critical risk factor for NAFLD, and suggest that supplementation with NAD+ substrates may be a promising therapeutic strategy to prevent and treat NAFLD.</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1111/bph.13513</identifier><identifier>PMID: 27174364</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>Aging ; Aging - drug effects ; Aging - metabolism ; Aging - pathology ; Animals ; Biosynthesis ; Humans ; Liver ; Liver - drug effects ; Liver - metabolism ; Liver diseases ; Male ; Mice ; Mice, Inbred C57BL ; Middle Aged ; NAD - antagonists & inhibitors ; NAD - deficiency ; NAD - metabolism ; Non-alcoholic Fatty Liver Disease - diagnosis ; Non-alcoholic Fatty Liver Disease - drug therapy ; Non-alcoholic Fatty Liver Disease - metabolism ; Research Paper ; Research Papers ; Rodents</subject><ispartof>British journal of pharmacology, 2016-08, Vol.173 (15), p.2352-2368</ispartof><rights>2016 The British Pharmacological Society</rights><rights>2016 The British Pharmacological Society.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3733-6efe98d48150f12a2a86066f146a9656adad9c01f524db97113446f3efb67c043</citedby><cites>FETCH-LOGICAL-c3733-6efe98d48150f12a2a86066f146a9656adad9c01f524db97113446f3efb67c043</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fbph.13513$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fbph.13513$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,315,733,786,790,891,1424,27957,27958,45609,45610,50923,51032,53827,53829</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27174364$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhou, Can‐Can</creatorcontrib><creatorcontrib>Yang, Xi</creatorcontrib><creatorcontrib>Hua, Xia</creatorcontrib><creatorcontrib>Liu, Jian</creatorcontrib><creatorcontrib>Fan, Mao‐Bing</creatorcontrib><creatorcontrib>Li, Guo‐Qiang</creatorcontrib><creatorcontrib>Song, Jie</creatorcontrib><creatorcontrib>Xu, Tian‐Ying</creatorcontrib><creatorcontrib>Li, Zhi‐Yong</creatorcontrib><creatorcontrib>Guan, Yun‐Feng</creatorcontrib><creatorcontrib>Wang, Pei</creatorcontrib><creatorcontrib>Miao, Chao‐Yu</creatorcontrib><title>Hepatic NAD+ deficiency as a therapeutic target for non‐alcoholic fatty liver disease in ageing</title><title>British journal of pharmacology</title><addtitle>Br J Pharmacol</addtitle><description>Background and Purpose
Ageing is an important risk factor of non‐alcoholic fatty liver disease (NAFLD). Here, we investigated whether the deficiency of nicotinamide adenine dinucleotide (NAD+), a ubiquitous coenzyme, links ageing with NAFLD.
Experimental Approach
Hepatic concentrations of NAD+, protein levels of nicotinamide phosphoribosyltransferase (NAMPT) and several other critical enzymes regulating NAD+ biosynthesis, were compared in middle‐aged and aged mice or patients. The influences of NAD+ decline on the steatosis and steatohepatitis were evaluated in wild‐type and H247A dominant‐negative, enzymically‐inactive NAMPT transgenic mice (DN‐NAMPT) given normal or high‐fat diet (HFD).
Key Results
Hepatic NAD+ level decreased in aged mice and humans. NAMPT‐controlled NAD+ salvage, but not de novo biosynthesis pathway, was compromised in liver of elderly mice and humans. Given normal chow, middle‐age DN‐NAMPT mice displayed systemic NAD+ reduction and had moderate NAFLD phenotypes, including lipid accumulation, enhanced oxidative stress, triggered inflammation and impaired insulin sensitivity in liver. All these NAFLD phenotypes, especially release of pro‐inflammatory factors, Kupffer cell accumulation, monocytes infiltration, NLRP3 inflammasome pathway and hepatic fibrosis (Masson's staining and α‐SMA staining), deteriorated further under HFD challenge. Oral administration of nicotinamide riboside, a natural NAD+ precursor, completely corrected these NAFLD phenotypes induced by NAD+ deficiency alone or HFD, whereas adenovirus‐mediated SIRT1 overexpression only partially rescued these phenotypes.
Conclusions and Implications
These results provide the first evidence that ageing‐associated NAD+ deficiency is a critical risk factor for NAFLD, and suggest that supplementation with NAD+ substrates may be a promising therapeutic strategy to prevent and treat NAFLD.</description><subject>Aging</subject><subject>Aging - drug effects</subject><subject>Aging - metabolism</subject><subject>Aging - pathology</subject><subject>Animals</subject><subject>Biosynthesis</subject><subject>Humans</subject><subject>Liver</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Liver diseases</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Middle Aged</subject><subject>NAD - antagonists & inhibitors</subject><subject>NAD - deficiency</subject><subject>NAD - metabolism</subject><subject>Non-alcoholic Fatty Liver Disease - diagnosis</subject><subject>Non-alcoholic Fatty Liver Disease - drug therapy</subject><subject>Non-alcoholic Fatty Liver Disease - metabolism</subject><subject>Research Paper</subject><subject>Research Papers</subject><subject>Rodents</subject><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNp1kc9u1DAQhy0EokvhwAsgS1xAKK0ndpzkglTKn0WqgAOcrVlnvOsqG6d2UrQ3HoFn5EnwsqUCJOYyh9-nTzP6MfYYxAnkOV2NmxOQFcg7bAGq1kUlG7jLFkKIugBomiP2IKVLIXJYV_fZUVlDraRWC4ZLGnHyln84e_2Cd-S89TTYHcfEkU8bijjSvAcmjGuauAuRD2H48e079jZsQp8jh9O0472_psg7nwgTcT9wXJMf1g_ZPYd9okc3-5h9efvm8_myuPj47v352UVhZS1loclR23SqgUo4KLHERgutHSiNra40dti1VoCrStWt2hpAKqWdJLfStRVKHrOXB-84r7bUWRqmiL0Zo99i3JmA3vydDH5j1uHaqFZVtYYseHYjiOFqpjSZrU-W-h4HCnMy0AjVaNWCzOjTf9DLMMchv7enZNs2ZSky9fxA2RhSiuRujwFh9sWZXJz5VVxmn_x5_S35u6kMnB6Ar76n3f9N5tWn5UH5Ey7kot4</recordid><startdate>201608</startdate><enddate>201608</enddate><creator>Zhou, Can‐Can</creator><creator>Yang, Xi</creator><creator>Hua, Xia</creator><creator>Liu, Jian</creator><creator>Fan, Mao‐Bing</creator><creator>Li, Guo‐Qiang</creator><creator>Song, Jie</creator><creator>Xu, Tian‐Ying</creator><creator>Li, Zhi‐Yong</creator><creator>Guan, Yun‐Feng</creator><creator>Wang, Pei</creator><creator>Miao, Chao‐Yu</creator><general>Blackwell Publishing Ltd</general><general>John Wiley and Sons Inc</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>7QP</scope><scope>7TK</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201608</creationdate><title>Hepatic NAD+ deficiency as a therapeutic target for non‐alcoholic fatty liver disease in ageing</title><author>Zhou, Can‐Can ; Yang, Xi ; Hua, Xia ; Liu, Jian ; Fan, Mao‐Bing ; Li, Guo‐Qiang ; Song, Jie ; Xu, Tian‐Ying ; Li, Zhi‐Yong ; Guan, Yun‐Feng ; Wang, Pei ; Miao, Chao‐Yu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3733-6efe98d48150f12a2a86066f146a9656adad9c01f524db97113446f3efb67c043</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Aging</topic><topic>Aging - drug effects</topic><topic>Aging - metabolism</topic><topic>Aging - pathology</topic><topic>Animals</topic><topic>Biosynthesis</topic><topic>Humans</topic><topic>Liver</topic><topic>Liver - drug effects</topic><topic>Liver - metabolism</topic><topic>Liver diseases</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Middle Aged</topic><topic>NAD - antagonists & inhibitors</topic><topic>NAD - deficiency</topic><topic>NAD - metabolism</topic><topic>Non-alcoholic Fatty Liver Disease - diagnosis</topic><topic>Non-alcoholic Fatty Liver Disease - drug therapy</topic><topic>Non-alcoholic Fatty Liver Disease - metabolism</topic><topic>Research Paper</topic><topic>Research Papers</topic><topic>Rodents</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhou, Can‐Can</creatorcontrib><creatorcontrib>Yang, Xi</creatorcontrib><creatorcontrib>Hua, Xia</creatorcontrib><creatorcontrib>Liu, Jian</creatorcontrib><creatorcontrib>Fan, Mao‐Bing</creatorcontrib><creatorcontrib>Li, Guo‐Qiang</creatorcontrib><creatorcontrib>Song, Jie</creatorcontrib><creatorcontrib>Xu, Tian‐Ying</creatorcontrib><creatorcontrib>Li, Zhi‐Yong</creatorcontrib><creatorcontrib>Guan, Yun‐Feng</creatorcontrib><creatorcontrib>Wang, Pei</creatorcontrib><creatorcontrib>Miao, Chao‐Yu</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhou, Can‐Can</au><au>Yang, Xi</au><au>Hua, Xia</au><au>Liu, Jian</au><au>Fan, Mao‐Bing</au><au>Li, Guo‐Qiang</au><au>Song, Jie</au><au>Xu, Tian‐Ying</au><au>Li, Zhi‐Yong</au><au>Guan, Yun‐Feng</au><au>Wang, Pei</au><au>Miao, Chao‐Yu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hepatic NAD+ deficiency as a therapeutic target for non‐alcoholic fatty liver disease in ageing</atitle><jtitle>British journal of pharmacology</jtitle><addtitle>Br J Pharmacol</addtitle><date>2016-08</date><risdate>2016</risdate><volume>173</volume><issue>15</issue><spage>2352</spage><epage>2368</epage><pages>2352-2368</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>These authors contributed equally to this work.</notes><abstract>Background and Purpose
Ageing is an important risk factor of non‐alcoholic fatty liver disease (NAFLD). Here, we investigated whether the deficiency of nicotinamide adenine dinucleotide (NAD+), a ubiquitous coenzyme, links ageing with NAFLD.
Experimental Approach
Hepatic concentrations of NAD+, protein levels of nicotinamide phosphoribosyltransferase (NAMPT) and several other critical enzymes regulating NAD+ biosynthesis, were compared in middle‐aged and aged mice or patients. The influences of NAD+ decline on the steatosis and steatohepatitis were evaluated in wild‐type and H247A dominant‐negative, enzymically‐inactive NAMPT transgenic mice (DN‐NAMPT) given normal or high‐fat diet (HFD).
Key Results
Hepatic NAD+ level decreased in aged mice and humans. NAMPT‐controlled NAD+ salvage, but not de novo biosynthesis pathway, was compromised in liver of elderly mice and humans. Given normal chow, middle‐age DN‐NAMPT mice displayed systemic NAD+ reduction and had moderate NAFLD phenotypes, including lipid accumulation, enhanced oxidative stress, triggered inflammation and impaired insulin sensitivity in liver. All these NAFLD phenotypes, especially release of pro‐inflammatory factors, Kupffer cell accumulation, monocytes infiltration, NLRP3 inflammasome pathway and hepatic fibrosis (Masson's staining and α‐SMA staining), deteriorated further under HFD challenge. Oral administration of nicotinamide riboside, a natural NAD+ precursor, completely corrected these NAFLD phenotypes induced by NAD+ deficiency alone or HFD, whereas adenovirus‐mediated SIRT1 overexpression only partially rescued these phenotypes.
Conclusions and Implications
These results provide the first evidence that ageing‐associated NAD+ deficiency is a critical risk factor for NAFLD, and suggest that supplementation with NAD+ substrates may be a promising therapeutic strategy to prevent and treat NAFLD.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>27174364</pmid><doi>10.1111/bph.13513</doi><tpages>17</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aging Aging - drug effects Aging - metabolism Aging - pathology Animals Biosynthesis Humans Liver Liver - drug effects Liver - metabolism Liver diseases Male Mice Mice, Inbred C57BL Middle Aged NAD - antagonists & inhibitors NAD - deficiency NAD - metabolism Non-alcoholic Fatty Liver Disease - diagnosis Non-alcoholic Fatty Liver Disease - drug therapy Non-alcoholic Fatty Liver Disease - metabolism Research Paper Research Papers Rodents |
| title | Hepatic NAD+ deficiency as a therapeutic target for non‐alcoholic fatty liver disease in ageing |
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