{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:16:39Z","timestamp":1790680599133,"version":"4.1.0"},"reference-count":59,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2016,6,27]],"date-time":"2016-06-27T00:00:00Z","timestamp":1466985600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2016,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Ageing is an important risk factor of non\u2010alcoholic fatty liver disease (NAFLD). Here, we investigated whether the deficiency of nicotinamide adenine dinucleotide (NAD<jats:sup>+<\/jats:sup>), a ubiquitous coenzyme, links ageing with NAFLD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Hepatic concentrations of NAD<jats:sup>+<\/jats:sup>, protein levels of nicotinamide phosphoribosyltransferase (NAMPT) and several other critical enzymes regulating NAD<jats:sup>+<\/jats:sup> biosynthesis, were compared in middle\u2010aged and aged mice or patients. The influences of NAD<jats:sup>+<\/jats:sup> decline on the steatosis and steatohepatitis were evaluated in wild\u2010type and H247A dominant\u2010negative, enzymically\u2010inactive NAMPT transgenic mice (DN\u2010NAMPT) given normal or high\u2010fat diet (HFD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Hepatic NAD<jats:sup>+<\/jats:sup> level decreased in aged mice and humans. NAMPT\u2010controlled NAD<jats:sup>+<\/jats:sup> salvage, but not <jats:italic>de novo<\/jats:italic> biosynthesis pathway, was compromised in liver of elderly mice and humans. Given normal chow, middle\u2010age DN\u2010NAMPT mice displayed systemic NAD<jats:sup>+<\/jats:sup> 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\u2010inflammatory factors, Kupffer cell accumulation, monocytes infiltration, NLRP3 inflammasome pathway and hepatic fibrosis (Masson's staining and \u03b1\u2010SMA staining), deteriorated further under HFD challenge. Oral administration of nicotinamide riboside, a natural NAD<jats:sup>+<\/jats:sup> precursor, completely corrected these NAFLD phenotypes induced by NAD<jats:sup>+<\/jats:sup> deficiency alone or HFD, whereas adenovirus\u2010mediated SIRT1 overexpression only partially rescued these phenotypes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>These results provide the first evidence that ageing\u2010associated NAD<jats:sup>+<\/jats:sup> deficiency is a critical risk factor for NAFLD, and suggest that supplementation with NAD<jats:sup>+<\/jats:sup> substrates may be a promising therapeutic strategy to prevent and treat NAFLD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13513","type":"journal-article","created":{"date-parts":[[2016,5,13]],"date-time":"2016-05-13T03:06:54Z","timestamp":1463108814000},"page":"2352-2368","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":195,"title":["Hepatic NAD<sup>+<\/sup> deficiency as a therapeutic target for non\u2010alcoholic fatty liver disease in ageing"],"prefix":"10.1111","volume":"173","author":[{"given":"Can\u2010Can","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Pharmacology Second Military Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Second Military Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Second Military Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital Second Military Medical University  Shanghai 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